A Stem-like Patient-Derived Ovarian Cancer Model of Platinum Resistance Reveals Dissociation of Stemness and Resistance.

To understand chemoresistance in the context of cancer stem cells (CSC), a cisplatin resistance model was developed using a high-grade serous ovarian cancer patient-derived, cisplatin-sensitive sample, PDX4. As a molecular subtype-specific stem-like cell line, PDX4 was selected for its representative features, including its histopathological and BRCA2 mutation status, and exposed to cisplatin in vitro. In the cisplatin-resistant cells, transcriptomics were carried out, and cell morphology, protein expression, and functional status were characterized. Additionally, potential signaling pathways involved in cisplatin resistance were explored. Our findings reveal the presence of distinct molecular signatures and phenotypic changes in cisplatin-resistant PDX4 compared to their sensitive counterparts. Surprisingly, we observed that chemoresistance was not inherently linked with increased stemness. In fact, although resistant cells expressed a combination of EMT and stemness markers, functional assays revealed that they were less proliferative, migratory, and clonogenic-features indicative of an underlying complex mechanism for cell survival. Furthermore, DNA damage tolerance and cellular stress management pathways were enriched. This novel, syngeneic model provides a valuable platform for investigating the underlying mechanisms of cisplatin resistance in a clinically relevant context, contributing to the development of targeted therapies tailored to combat resistance in stem-like ovarian cancer.

Activation of human STING by a molecular glue-like compound.

Stimulator of interferon genes (STING) is a dimeric transmembrane adapter protein that plays a key role in the human innate immune response to infection and has been therapeutically exploited for its antitumor activity. The activation of STING requires its high-order oligomerization, which could be induced by binding of the endogenous ligand, cGAMP, to the cytosolic ligand-binding domain. Here we report the discovery through functional screens of a class of compounds, named NVS-STGs, that activate human STING. Our cryo-EM structures show that NVS-STG2 induces the high-order oligomerization of human STING by binding to a pocket between the transmembrane domains of the neighboring STING dimers, effectively acting as a molecular glue. Our functional assays showed that NVS-STG2 could elicit potent STING-mediated immune responses in cells and antitumor activities in animal models.

Impact of Co-occurring Cancer-Related and Wound-Specific Symptoms on Functional Performance Among Patients With Advanced Cancer and Malignant Fungating Wounds: An Exploratory, Observational Study.

PURPOSE: The purpose of this study was to examine the impact of co-occurring symptoms in patients with advanced cancer and malignant fungating wounds (MFWs) on palliative and functional performance, and the feasibility of collecting self-reported data in this population. DESIGN: This was an exploratory, observational study. Quantitative surveys and qualitative semistructured interviews using a phenomenological approach were employed. SUBJECTS AND SETTING: The sample comprised 5 adults with advanced breast, oral, and ovarian cancer and MFWs. Participants were recruited from an urban outpatient cancer center, hospice, and wound center located in the Northeastern United States. METHODS: Demographic and clinical characteristics were collected, and self-reported symptom and functional performance data measured. Descriptive statistics, T scores, confidence intervals, and standard deviation were calculated for quantitative data. One-to-one semistructured interviews were conducted by the first author to gain deeper understanding of participants' symptom experience. Qualitative data were analyzed using an iterative and inductive thematic data analysis method to identify major themes. RESULTS: The mean cancer-related and wound-specific symptom occurrence was 17 (SD = 5.56) and 4 (SD = 1.26), respectively. Distressing, extensive co-occurring symptom burdens were experienced by all participants; they also reported poor functional performance and diminished palliative performance. Qualitative findings supported quantitative results. CONCLUSIONS: Findings suggest that co-occurring cancer-related and wound-specific symptoms have incremental and negative impact on functional performance. The use of multiple data collection methods was feasible, including self-reported data in this advanced cancer population.

Complex Care Needs at the End of Life for Seriously Ill Adults With Multiple Chronic Conditions.

Understanding the complex care needs of seriously ill adults with multiple chronic conditions with and without cancer is critical for the delivery of high-quality serious illness and palliative care at the end of life. The objective of this secondary data analysis of a multisite randomized clinical trial in palliative care was to elucidate the clinical profile and complex care needs of seriously ill adults with multiple chronic conditions and to highlight key differences among those with and without cancer at the end of life. Of the 213 (74.2%) older adults who met criteria for multiple chronic conditions (eg, 2 or more chronic conditions requiring regular care with limitations of daily living), 49% had a diagnosis of cancer. Hospice enrollment was operationalized as an indicator for severity of illness and allowed for the capture of complex care needs of those deemed to be nearing the end of life. Individuals with cancer had complex symptomatology with a higher prevalence of nausea, drowsiness, and poor appetite and end of life and lower hospice enrollment. Individuals with multiple chronic conditions without cancer had lower functional status, greater number of medications, and higher hospice enrollment. The care of seriously ill older adults with multiple chronic conditions requires tailored approaches to improve outcomes and quality of care across health care settings, particularly at the end of life.

Multiple Chronic Conditions among Seriously Ill Adults Receiving Palliative Care.

The objective of this study was to characterize multiple chronic conditions (MCCs) among seriously ill adults receiving palliative care at the end of life. A latent class analysis was conducted to identify latent subgroups of seriously ill older adults based on a baseline Charlson comorbidity index (CCI) measurement, a measure of comorbidity burden, and mortality risk. The three latent subgroups were: (1) low to moderate CCI with MCC, (2) high CCI with MCC, and (3) high CCI and metastatic cancer. The "low to moderate CCI and MCC" subgroup included older adults with chronic obstructive pulmonary disease (COPD), cardiovascular disease, congestive heart failure, myocardial infarction, dementia, diabetes, and lymphoma. A "high CCI and MCC" subgroup included individuals with severe illness including liver or renal disease among other MCCs. A "high CCI and metastatic cancer" included all participants with metastatic cancer. This study sheds light on the MCC profile of seriously ill adults receiving palliative care.

Neurotrophin Pathway Receptors NGFR and TrkA Control Perineural Invasion, Metastasis, and Pain in Oral Cancer.

Oral squamous cell carcinoma (OSCC) patients suffer from poor survival due to metastasis or locoregional recurrence, processes that are both facilitated by perineural invasion (PNI). OSCC has higher rates of PNI than other cancer subtypes, with PNI present in 80% of tumors. Despite the impact of PNI on oral cancer prognosis and pain, little is known about the genes that drive PNI, which in turn drive pain, invasion, and metastasis. In this study, clinical data, preclinical, and in vitro models are leveraged to elucidate the role of neurotrophins in OSCC metastasis, PNI, and pain. The expression data in OSCC patients with metastasis, PNI, or pain demonstrate dysregulation of neurotrophin genes. TrkA and nerve growth factor receptor (NGFR) are focused, two receptors that are activated by NGF, a neurotrophin expressed at high levels in OSCC. It is demonstrated that targeted knockdown of these two receptors inhibits proliferation and invasion in an in vitro and preclinical model of OSCC, and metastasis, PNI, and pain. It is further determined that TrkA knockdown alone inhibits thermal hyperalgesia, whereas NGFR knockdown alone inhibits mechanical allodynia. Collectively the results highlight the ability of OSCC to co-opt different components of the neurotrophin pathway in metastasis, PNI, and pain.

Multimorbidity patterns in adult day health center clients with dementia: a latent class analysis.

BACKGROUND: Persons living with dementia (PLWD) in adult day centers (ADCs) represent a complex and vulnerable population whose well-being is at risk based on numerous factors. Greater knowledge of the interaction between dementia, chronic conditions, and social determinants of health would enable ADCs to identify and target the use of their resources to better support clients in need of in-depth intervention. The purpose of this paper is to (a) classify PLWD in ADCs according to their level of medical complexity and (b) identify the demographic, functional, and clinical characteristics of those with the highest degree of medical complexity. METHODS: This was a secondary data analysis of 3052 clients with a dementia diagnosis from 53 ADCs across the state of California between 2012 and 2019. The most common diagnosis codes were organized into 28 disease categories to enable a latent class analysis (LCA). Chi-square test, analysis of variance (ANOVA), and Kruskal-Wallis tests were conducted to examine differences among latent classes with respect to clinical and functional characteristics. RESULTS: An optimal 4-class solution was chosen to reflect chronic conditions among PLWD: high medical complexity, moderate medical complexity, low medical complexity, and no medical complexity. Those in the high medical complexity were taking an average of 12.72 (+/- 6.52) medications and attending the ADC an average of 3.98 days (+/- 1.31) per week-values that exceeded any other class. They also experienced hospitalizations more than any other group (19.0%) and met requirements for the nursing facility level of care (77.4%). In addition, the group experienced the greatest frequency of bladder (57.5%) and bowel (15.7%) incontinence. CONCLUSIONS: Our results illustrate a high degree of medical complexity among PLWD in ADCs. A majority of PLWD not only have multimorbidity but are socially disadvantaged. Our results demonstrate that a comprehensive multidisciplinary approach that involves community partners such as ADCs is critically needed that addresses functional decline, loneliness, social isolation, and multimorbidity which can negatively impact PLWD.

Associations of insomnia symptoms with sociodemographic, clinical, and lifestyle factors in persons with HF: Health and retirement study.

Insomnia symptoms are very common in persons with heart failure (HF). However, many of the correlates and predictors of insomnia symptoms in this population remain unclear. The purpose of this study is to investigate the associations of sociodemographic, clinical, and lifestyle factors with insomnia symptoms in persons with HF. A theoretical framework was adapted from the neurocognitive model of chronic insomnia to guide the study. Data from the health and retirement study were used for the analysis. Parametric and nonparametric bivariate and multivariate analyses were conducted to investigate these associations. Age, depressive symptoms, comorbidity, dyspnea, pain, and smoking had significant bivariate associations with all insomnia symptoms. Race, Hispanic ethnicity, marital status, household income, poverty, and physical activity were associated with difficulty initiating sleep (DIS) and early morning awakening (EMA). Female sex, education, and alcohol consumption had a significant bivariate association with DIS. Sleep-disordered breathing and body mass index were significantly associated with EMA. Multivariate analysis suggested that depressive symptoms, comorbidity, dyspnea, and pain had independent associations with each insomnia symptom. Age explained DIS and difficulty maintaining sleep, and significant interaction effects between age and physical activity on DIS and EMA were revealed. Results suggest that insomnia symptoms are associated with several sociodemographic, clinical, and lifestyle factors. Age below 70 years, depressive symptoms, comorbidity, dyspnea, and pain might be considered as a phenotype to identify persons with HF who are at increased risk for insomnia symptoms.

A Web- and Mobile-Based Intervention for Women Treated for Breast Cancer to Manage Chronic Pain and Symptoms Related to Lymphedema: Results of a Randomized Clinical Trial.

BACKGROUND: The-Optimal-Lymph-Flow (TOLF) is a patient-centered, web- and mobile-based mHealth system that delivers safe, easy, and feasible digital therapy of lymphatic exercises and limb mobility exercises. OBJECTIVE: The purpose of this randomized clinical trial (RCT) was to evaluate the effectiveness of the web- and mobile-based TOLF system for managing chronic pain and symptoms related to lymphedema. The primary outcome includes pain reduction, and the secondary outcomes focus on symptom relief, limb volume difference measured by infrared perometer, BMI, and quality of life (QOL) related to pain. We hypothesized that participants in the intervention group would have improved pain and symptom experiences, limb volume difference, BMI, and QOL. METHODS: A parallel RCT with a control-experimental, pre- and posttest, and repeated-measures design were used. A total of 120 patients were recruited face-to-face at the point of care during clinical visits. Patients were randomized according to pain in a 1:1 ratio into either the arm precaution (AP) control group to improve limb mobility and arm protection or The-Optimal-Lymph flow (TOLF) intervention group to promote lymph flow and limb mobility. Trial outcomes were evaluated at baseline and at week 12 after the intervention. Descriptive statistics, Fisher exact tests, Wilcoxon rank-sum tests, t test, and generalized linear mixed effects models were performed for data analysis. RESULTS: At the study endpoint of 12 weeks, significantly fewer patients in the TOLF intervention group compared with the AP control group reported chronic pain (45% [27/60] vs 70% [42/60]; odds ratio [OR] 0.39, 95% CI 0.17-0.90; P=.02). Patients who received the TOLF intervention were significantly more likely to achieve a complete reduction in pain (50% [23/46] vs 22% [11/51]; OR 3.56, 95% CI 1.39-9.76; P=.005) and soreness (43% [21/49] vs 22% [11/51]; OR 2.60, 95% CI 1.03-6.81; P=.03). Significantly lower median severity scores were found in the TOLF group for chronic pain (MedTOLF=0, IQR 0-1 vs MedAP=1, IQR 0-2; P=.02) and general bodily pain (MedTOLF=1, IQR=0-1.5 vs MedAP=1, IQR 1-3; P=.04). Compared with the AP control group, significantly fewer patients in the TOLF group reported arm/hand swelling (P=.04), heaviness (P=.03), redness (P=.03), and limited movement in shoulder (P=.02) and arm (P=.03). No significant differences between the TOLF and AP groups were found in complete reduction of aching (P=.12) and tenderness (P=.65), mean numbers of lymphedema symptom reported (P=.11), ≥5% limb volume differences (P=.48), and BMI (P=.12). CONCLUSIONS: The TOLF intervention had significant benefits for breast cancer survivors to manage chronic pain, soreness, general bodily pain, arm/hand swelling, heaviness, and impaired limb mobility. The intervention resulted in a 13% reduction (from 40% [24/60] to 27% [16/60]) in proportions of patients who took pain medications compared with the AP control group, which had a 5% increase (from 40% [24/60] to 45% [27/60]). A 12% reduction (from 27% [16/60] to 15% [9/60]) in proportions of patients with ≥5% limb volume differences was found in the TOLF intervention, while a 5% increase in the AP control group (from 40% [24/60] to 45% [27/60]) was found. In conclusion, the TOLF intervention can be a better choice for breast cancer survivors to reduce chronic pain and limb volume. TRIAL REGISTRATION: Clinicaltrials.gov NCT02462226; https://clinicaltrials.gov/ct2/show/NCT02462226. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.2196/resprot.5104.

Soluble epoxide hydrolase inhibitor can protect the femoral head against tobacco smoke exposure-induced osteonecrosis in spontaneously hypertensive rats.

Exposure to tobacco smoke (TS) has been considered a risk factor for osteonecrosis of the femoral head (ONFH). Soluble epoxide hydrolase inhibitors (sEHIs) have been found to reduce inflammation and oxidative stress in a variety of pathologies. This study was designed to assess the effect of sEHI on the development of ONFH phenotypes induced by TS exposure in spontaneously hypertensive (SH) rats. SH and normotensive Wistar Kyoto (WKY) rats were exposed to filtered air (FA) or TS (80 mg/m3 particulate concentration) 6 h/day, 3 days/week for 8 weeks. During this period, sEHI was delivered through drinking water at a concentration of 6 mg/L. Histology, immunohistochemistry, and micro-CT morphometry were performed for phenotypic evaluation. As results, TS exposure induced significant increases in adipocyte area, bone specific surface (BS/BV), and trabecular separation (Tb.SP), as well as significant decreases in bone mineral density (BMD), percent trabecular area (Tb.Ar), HIF-1a expression, bone volume fraction (BV/TV), trabecular numbers (Tb.N), and trabecular thickness (Tb.Th) in both SH and WKY rats. However, the protective effects of sEHI were mainly observed in TS-exposed SH rats, specifically in the density of osteocytes, BMD, Tb.Ar, HIF-1a expression, BV/TV, BS/BV, Tb.N, and Tb.SP. Our study confirms that TS exposure can induce ONFH especially in SH rats, and suggests that sEHI therapy may protect against TS exposure-induced osteonecrotic changes in the femoral head.

Brush swab as a noninvasive surrogate for tissue biopsies in epigenomic profiling of oral cancer.

BACKGROUND: Oral squamous cell carcinoma (OSCC) has poor survival rates. There is a pressing need to develop more precise risk assessment methods to tailor clinical treatment. Epigenome-wide association studies in OSCC have not produced a viable biomarker. These studies have relied on methylation array platforms, which are limited in their ability to profile the methylome. In this study, we use MethylCap-Seq (MC-Seq), a comprehensive methylation quantification technique, and brush swab samples, to develop a noninvasive, readily translatable approach to profile the methylome in OSCC patients. METHODS: Three OSCC patients underwent collection of cancer and contralateral normal tissue and brush swab biopsies, totaling 4 samples for each patient. Epigenome-wide DNA methylation quantification was performed using the SureSelectXT Methyl-Seq platform. DNA quality and methylation site resolution were compared between brush swab and tissue samples. Correlation and methylation value difference were determined for brush swabs vs. tissues for each respective patient and site (i.e., cancer or normal). Correlations were calculated between cancer and normal tissues and brush swab samples for each patient to determine the robustness of DNA methylation marks using brush swabs in clinical biomarker studies. RESULTS: There were no significant differences in DNA yield between tissue and brush swab samples. Mapping efficiency exceeded 90% across all samples, with no differences between tissue and brush swabs. The average number of CpG sites with at least 10x depth of coverage was 2,716,674 for brush swabs and 2,903,261 for tissues. Matched tissue and brush swabs had excellent correlation (r = 0.913 for cancer samples and r = 0.951 for normal samples). The methylation profile of the top 1000 CpGs was significantly different between cancer and normal samples (mean p-value = 0.00021) but not different between tissues and brush swabs (mean p-value = 0.11). CONCLUSIONS: Our results demonstrate that MC-Seq is an efficient platform for epigenome profiling in cancer biomarker studies, with broader methylome coverage than array-based platforms. Brush swab biopsy provides adequate DNA yield for MC-Seq, and taken together, our findings set the stage for development of a non-invasive methylome quantification technique for oral cancer with high translational potential.

Latent Class Analysis of Symptom Burden Among Seriously Ill Adults at the End of Life.

BACKGROUND: Serious illness is characterized by high symptom burden that negatively affects quality of life (QOL). Although palliative care research has highlighted symptom burden in seriously ill adults with cancer, symptom burden among those with noncancer serious illness and multiple chronic conditions has been understudied. Latent class analysis is a statistical method that can be used to better understand the relationship between severity of symptom burden and covariates, such as the presence of multiple chronic conditions. Although latent class analysis has been used to highlight subgroups of seriously ill adults with cancer based on symptom clusters, none have incorporated multiple chronic conditions. OBJECTIVES: The objectives of this study were to (a) describe the demographic and baseline characteristics of seriously ill adults at the end of life in a palliative care cohort, (b) identify latent subgroups of seriously ill individuals based on severity of symptom burden, and (c) examine variables associated with latent subgroup membership, such as QOL, functional status, and the presence of multiple chronic conditions. METHODS: A secondary data analysis of a palliative care clinical trial was conducted. The latent class analysis was based on the Edmonton Symptom Assessment System, which measures nine symptoms on a scale of 0-10 (e.g., pain, fatigue, nausea, depression, anxiousness, drowsiness, appetite, well-being, and shortness of breath). Clinically significant cut-points for symptom severity were used to categorize each symptom item in addition to a categorized total score. RESULTS: Three latent subgroups were identified (e.g., low, moderate, and high symptom burden). Lower overall QOL was associated with membership in the moderate and high symptom burden subgroups. Multiple chronic conditions were associated with statistically significant membership in the high symptom burden latent subgroup. Older adults between 65 and 74 years had a lower likelihood of moderate or high symptom burden subgroup membership compared to the low symptom burden class. DISCUSSION: Lower QOL was associated with high symptom burden. Multiple chronic conditions were associated with high symptom burden, which underlines the clinical complexity of serious illness. Palliative care at the end of life for seriously ill adults with high symptom burden must account for the presence of multiple chronic conditions.

Model-Based Patterns of Lymphedema Symptomatology: Phenotypic and Biomarker Characterization.

PURPOSE OF THE STUDY: More than 50% of breast cancer survivors without a diagnosis of lymphedema suffer daily from numerous and co-occurring lymphedema symptoms. This study aimed to identify lymphedema symptom patterns and the association of such patterns with phenotypic characteristics and biomarkers using latent class analysis (LCA). A prospective, descriptive, and repeated-measure design was used to enroll 140 women and collect data. RECENT FINDINGS: LCA identified three distinct lymphedema symptom classes at 8 weeks and 12 months post-surgery: low, moderate, and severe symptom classes and associated phenotypic characteristics. Participants were more likely to be in the severe symptom classes at 12 months post-surgery if they had lower education level, cording, an axillary syndrome at 8 weeks post-surgery, neoadjuvant chemotherapy, and radiation. SUMMARY: Pre-surgery level of IL1-a, IL-6, IL-8, and VEGF was associated with the severe symptom class at 8 weeks post-surgery, suggesting that such biomarkers may be used to predict risk for lymphedema symptoms.

The REASON score: an epigenetic and clinicopathologic score to predict risk of poor survival in patients with early stage oral squamous cell carcinoma.

BACKGROUND: Oral squamous cell carcinoma (OSCC) is a capricious cancer with poor survival rates, even for early-stage patients. There is a pressing need to develop more precise risk assessment methods to appropriately tailor clinical treatment. Genome-wide association studies have not produced a viable biomarker. However, these studies are limited by using heterogeneous cohorts, not focusing on methylation although OSCC is a heavily epigenetically-regulated cancer, and not combining molecular data with clinicopathologic data for risk prediction. In this study we focused on early-stage (I/II) OSCC and created a risk score called the REASON score, which combines clinicopathologic characteristics with a 12-gene methylation signature, to predict the risk of 5-year mortality. METHODS: We combined data from an internal cohort (n = 515) and The Cancer Genome Atlas (TCGA) cohort (n = 58). We collected clinicopathologic data from both cohorts to derive the non-molecular portion of the REASON score. We then analyzed the TCGA cohort DNA methylation data to derive the molecular portion of the risk score. RESULTS: 5-year disease specific survival was 63% for the internal cohort and 86% for the TCGA cohort. The clinicopathologic features with the highest predictive ability among the two the cohorts were age, race, sex, tobacco use, alcohol use, histologic grade, stage, perineural invasion (PNI), lymphovascular invasion (LVI), and margin status. This panel of 10 non-molecular features predicted 5-year mortality risk with a concordance (c)-index = 0.67. Our molecular panel consisted of a 12-gene methylation signature (i.e., HORMAD2, MYLK, GPR133, SOX8, TRPA1, ABCA2, HGFAC, MCPH1, WDR86, CACNA1H, RNF216, CCNJL), which had the most significant differential methylation between patients who survived vs. died by 5 years. All 12 genes have already been linked to survival in other cancers. Of the genes, only SOX8 was previously associated with OSCC; our study was the first to link the remaining 11 genes to OSCC survival. The combined molecular and non-molecular panel formed the REASON score, which predicted risk of death with a c-index = 0.915. CONCLUSIONS: The REASON score is a promising biomarker to predict risk of mortality in early-stage OSCC patients. Validation of the REASON score in a larger independent cohort is warranted.

Co-Occurrence of Symptoms and Gut Microbiota Composition Before Neoadjuvant Chemotherapy and Radiation Therapy for Rectal Cancer: A Proof of Concept.

PURPOSE: To examine a) whether there are significant differences in gut microbial diversity and in the abundance of gut microbial taxa; and b) differences in predicted functional pathways of the gut microbiome between those participants with high co-occurring symptoms and those with low co-occurring symptoms, prior to neoadjuvant chemotherapy and radiation therapy (CRT) for rectal cancer. METHODS: Rectal cancer patients (n = 41) provided stool samples for 16 S rRNA gene sequencing and symptom ratings for fatigue, sleep disturbance, and depressive symptoms prior to CRT. Descriptive statistics were computed for symptoms. Gut microbiome data were analyzed using QIIME2, LEfSe, and the R statistical package. RESULTS: Participants with high co-occurring symptoms (n = 19) had significantly higher bacterial abundances of Ezakiella, Clostridium sensu stricto, Porphyromonas, Barnesiella, Coriobacteriales Incertae Sedis, Synergistiaceae, Echerichia-Shigella, and Turicibacter compared to those with low co-occurring symptoms before CRT (n = 22). Biosynthesis pathways for lipopolysaccharide, L-tryptophan, and colanic acid building blocks were enriched in participants with high co-occurring symptoms. Participants with low co-occurring symptoms showed enriched abundances of Enterococcus and Lachnospiraceae, as well as pathways for ß-D-glucoronosides, hexuronide/hexuronate, and nicotinate degradation, methanogenesis, and L-lysine biosynthesis. CONCLUSION: A number of bacterial taxa and predicted functional pathways were differentially abundant in patients with high co-occurring symptoms compared to those with low co-occurring symptoms before CRT for rectal cancer. Detailed examination of bacterial taxa and pathways mediating co-occurring symptoms is warranted.

Habitual physical activity patterns in a nationally representative sample of U.S. adults.

Physical inactivity is a leading determinant of noncommunicable diseases. Yet, many adults remain physically inactive. Physical activity guidelines do not account for the multidimensionality of physical activity, such as the type or variety of physical activity behaviors. This study identified patterns of physical activity across multiple dimensions (e.g., frequency, duration, and variety) using a nationally representative sample of adults. Sociodemographic characteristics, health behaviors, and clinical characteristics associated with each physical activity pattern were defined. Multivariate finite mixture modeling was used to identify patterns of physical activity among 2003-2004 and 2005-2006 adult National Health and Nutrition Examination Survey participants. Chi-square tests were used to identify sociodemographic differences within each physical activity cluster and test associations between the physical activity clusters with health behaviors and clinical characteristics. Five clusters of physical activity patterns were identified: (a) low frequency, short duration (n = 730, 13%); (b) low frequency, long duration (n = 392, 7%); (c) daily frequency, short duration (n = 3,011, 55%); (d) daily frequency, long duration (n = 373, 7%); and (e) high frequency, average duration (n = 964, 18%). Walking was the most common form of activity; highly active adults engaged in more varied types of activity. High-activity clusters were comprised of a greater proportion of younger, White, nonsmoking adult men reporting moderate alcohol use without mobility problems or chronic health conditions. Active females engaged in frequent short bouts of activity. Data-driven approaches are useful for identifying clusters of physical activity that encompass multiple dimensions of activity. These activity clusters vary across sociodemographic and clinical subgroups.

Limb Volume Changes and Activities of Daily Living: A Prospective Study.

Background: Breast cancer-related lymphedema (BCRL) limits the movements of patients' limbs, which leads to a diminished ability to achieve essential activities of daily living (ADLs). The purpose of this study was to examine the associations between limb volume changes from the baseline before breast cancer surgery and self-reported difficulty in performing ADLs at 12 months following cancer surgery. We hypothesized that a positive association existed between limb volume changes from the baseline and self-reported difficulty in performing ADLs at 12 months following breast cancer surgery. Methods and Results: The data of the present study were part of a larger study with 140 breast cancer patients recruited before breast cancer surgery and followed up during their first year of treatment. Patients with more than 10% limb volume increase reported more frequent distress in performing 13 ADL items, compared with patients whose limb volume increased by 5%-10%. Regression analysis showed a significant increase in the odds ratio of reporting difficulty in ADLs compared with the group with less than 5% limb volume increase. Conclusion: Overall, patients with a greater limb volume increase underwent more difficulty performing ADLs. Patients reported more difficulty in performing ADLs even with 5%-10% limb volume increase. Currently, there is no standardized guideline to diagnose BCRL, although previous evidence suggests a limb volume increase greater than 10% as a criterion for BCRL. The findings from the present study suggest a more precise and clinically meaningful criteria for diagnosing BCRL to accommodate those with 5%-10% increase in limb volume.

Targeting the endothelin axis as a therapeutic strategy for oral cancer metastasis and pain.

Metastasis reduces survival in oral cancer patients and pain is their greatest complaint. We have shown previously that oral cancer metastasis and pain are controlled by the endothelin axis, which is a pathway comprised of the endothelin A and B receptors (ETAR and ETBR). In this study we focus on individual genes of the pathway, demonstrating that the endothelin axis genes are methylated and dysregulated in cancer tissue. Based on these findings in patients, we hypothesize that ETAR and ETBR play dichotomous roles in oral carcinogenesis and pain, such that ETAR activation and silenced ETBR expression result in increased carcinogenesis and pain. We test a treatment strategy that targets the dichotomous functions of the two receptors by inhibiting ETAR with macitentan, an ETAR antagonist approved for treatment of pulmonary hypertension, and re-expressing the ETBR gene with adenovirus transduction, and determine the treatment effect on cancer invasion (i.e., metastasis), proliferation and pain in vitro and in vivo. We demonstrate that combination treatment of macitentan and ETBR gene therapy inhibits invasion, but not proliferation, in cell culture and in a mouse model of tongue cancer. Furthermore, the treatment combination produces an antinociceptive effect through inhibition of endothelin-1 mediated neuronal activation, revealing the analgesic potential of macitentan. Our treatment approach targets a pathway shown to be dysregulated in oral cancer patients, using gene therapy and repurposing an available drug to effectively treat both oral cancer metastasis and pain in a preclinical model.

Accumulation of Anthocyanins and Other Phytochemicals in American Elderberry Cultivars during Fruit Ripening and its Impact on Color Expression.

American elderberry (Sambucus canadensis) is a plant native to North America with anthocyanin-rich fruits. Our objective was to investigate the effects of cultivar and ripeness on the phytochemical characteristics of its fruits and the corresponding color performance. Cultivars 'Adams', 'Johns', 'Nova', 'Wyldewood', and 'York' were examined for their °Brix, pH, anthocyanin (pH-differential method), and phenolic content (Folin-Ciocalteau method). Extract composition were analyzed by uHPLC-PDA-MS/MS. Color and spectra were determined using a plate reader. All characteristics evaluated were significantly affected by ripeness and cultivar, except for °Brix and total phenolic content, which did not vary significantly among cultivars. Most anthocyanins (63-72%) were acylated with p-coumaric acid, with cyanidin-3-(trans)-coumaroylsambubioside-5-glucoside the most predominant. The proportion of acylated anthocyanins was the only characteristic evaluated that decreased during ripening (from 80 to 70%). Extract from fully-ripened fruits exhibited red (lvis-max ~520 nm) and blue hues (lvis-max ~600 nm) at acidic and alkaline pH, respectively. Extracts from half-ripe fruit rendered yellowish tones and overall dull color. C-18 semi-purified extracts displayed higher color saturation (smaller L* and larger C*ab) than crude extracts. The vibrant and broad color expression of fully-ripened fruit extract, especially after C-18 purification, suggests this North American native plant as a promising natural colorant source.

An Adapted Conceptual Model Integrating Palliative Care in Serious Illness and Multiple Chronic Conditions.

OBJECTIVE: Seriously ill adults with multiple chronic conditions (MCC) who receive palliative care may benefit from improved symptom burden, health care utilization and cost, caregiver stress, and quality of life. To guide research involving serious illness and MCC, palliative care can be integrated into a conceptual model to develop future research studies to improve care strategies and outcomes in this population. METHODS: The adapted conceptual model was developed based on a thorough review of the literature, in which current evidence and conceptual models related to serious illness, MCC, and palliative care were appraised. Factors contributing to patients' needs, services received, and service-related variables were identified. Relevant patient outcomes and evidence gaps are also highlighted. RESULTS: Fifty-eight articles were synthesized to inform the development of an adapted conceptual model including serious illness, MCC, and palliative care. Concepts were organized into 4 main conceptual groups, including Factors Affecting Needs (sociodemographic and social determinants of health), Factors Affecting Services Received (health system; research, evidence base, dissemination, and health policy; community resources), Service-Related Variables (patient visits, service mix, quality of care, patient information, experience), and Outcomes (symptom burden, quality of life, function, advance care planning, goal-concordant care, utilization, cost, death, site of death, satisfaction). DISCUSSION: The adapted conceptual model integrates palliative care with serious illness and multiple chronic conditions. The model is intended to guide the development of research studies involving seriously ill adults with MCC and aid researchers in addressing relevant evidence gaps.