Prognostic implication of methylation-based circulating tumor DNA detection prior to surgery in stage I non-small cell lung cancer.

BACKGROUND: Circulating tumor DNA (ctDNA) positivity at diagnosis, which is associated with worse outcomes in multiple solid tumors including stage I-III non-small cell lung cancer (NSCLC), may have utility to guide (neo)adjuvant therapy. METHODS: In this retrospective study, 260 patients with clinical stage I NSCLC (180 adenocarcinoma, 80 squamous cell carcinoma) were allocated (2:1) to high- and low-risk groups based on relapse versus disease-free status ≤5 years post-surgery. We evaluated the association of preoperative ctDNA detection by a plasma-only targeted methylation-based multi-cancer early detection (MCED) test with NSCLC relapse ≤5 years post-surgery in the overall population, followed by histology-specific subgroup analyses. RESULTS: Across clinical stage I patients, preoperative ctDNA detection did not associate with relapse within 5 years post-surgery. Sub-analyses confined to lung adenocarcinoma suggested a histology-specific association between ctDNA detection and outcome. In this group, ctDNA positivity tended to associate with relapse within 2 years, suggesting prognostic implications of MCED test positivity may be histology- and time-dependent in stage I NSCLC. Preoperative ctDNA detection was associated with upstaging of clinical stage I to pathological stage II-III NSCLC. CONCLUSIONS: Our findings suggest preoperative ctDNA detection in patients with resectable clinical stage I NSCLC using MCED, a pan-cancer screening test developed for use in an asymptomatic population, has no detectable prognostic value for relapse ≤5 years post-surgery. MCED detection may be associated with early adenocarcinoma relapse and increased pathological upstaging rates in stage I NSCLC. However, given the exploratory nature of these findings, independent validation is required.

Identifying Sex-Specific Serum Patterns of Alzheimer's Mice through Deep TMT Profiling and a Concentration-Dependent Concatenation Strategy.

Alzheimer's disease (AD) is the most prevalent form of dementia, disproportionately affecting women in disease prevalence and progression. Comprehensive analysis of the serum proteome in a common AD mouse model offers potential in identifying possible AD pathology- and gender-associated biomarkers. Here, we introduce a multiplexed, nondepleted mouse serum proteome profiling via tandem mass-tag (TMTpro) labeling. The labeled sample was separated into 475 fractions using basic reversed-phase liquid chromatography (RPLC), which were categorized into low-, medium-, and high-concentration fractions for concatenation. This concentration-dependent concatenation strategy resulted in 128 fractions for acidic RPLC-tandem mass spectrometry (MS/MS) analysis, collecting ∼5 million MS/MS scans and identifying 3972 unique proteins (3413 genes) that cover a dynamic range spanning at least 6 orders of magnitude. The differential expression analysis between wild type and the commonly used AD model (5xFAD) mice exhibited minimal significant protein alterations. However, we detected 60 statistically significant (FDR < 0.05), sex-specific proteins, including complement components, serpins, carboxylesterases, major urinary proteins, cysteine-rich secretory protein 1, pregnancy-associated murine protein 1, prolactin, amyloid P component, epidermal growth factor receptor, fibrinogen-like protein 1, and hepcidin. The results suggest that our platform possesses the sensitivity and reproducibility required to detect sex-specific differentially expressed proteins in mouse serum samples.

Predicting Probability of Response to Tumor Necrosis Factor Inhibitors for Individual Patients With Ankylosing Spondylitis.

Importance: Tumor necrosis factor inhibitors (TNFis) have revolutionized the management of ankylosing spondylitis (AS); however, the lack of notable clinical responses in approximately one-half of patients suggests important heterogeneity in treatment response. Identifying patients likely to respond or not respond to TNFis could provide opportunities to personalize treatment strategies. Objective: To develop models of the probability of short-term response to TNFi treatment in individual patients with active AS. Design, Setting, and Participants: This is a retrospective cohort study using data of the TNFi group (ie, treatment group) from 10 randomized clinical trials (RCTs) of TNFi treatment among patients with active AS, conducted from 2002 to 2016. Participants were adult patients with active AS who failed nonsteroidal anti-inflammatory drugs. Included RCTs were phase 3 and 4 studies that assessed the efficacy of an originator TNFi at week 12 and/or week 24, either compared with placebo or an antirheumatic drug. The cohort was divided into a training and a testing set. Data analysis was conducted from July 1, 2019, to November 30, 2020. Exposures: All included patients received an originator TNFi for at least 12 weeks. Main Outcomes and Measures: Outcomes included major response and no response based on the change of AS Disease Activity Score at 12 weeks. Machine learning algorithms were applied to estimate the probability of having major response and no response for individual patients. Results: The study included 1899 participants from 10 trials. The training set included 1207 individuals (mean [SD] age, 39 [12] years; 908 [75.2%] men), of whom 407 (33.7%) had major response and 414 (34.3%) had no response. In the reduced logistic regression models, accuracy was 0.74 for major response and 0.75 for no response. The probability of major response increased with higher C-reactive protein (CRP) level, patient global assessment (PGA), and Bath AS Disease Activity Index (BASDAI) question 2 score and decreased with higher body mass index (BMI) and Bath AS Functional Index (BASFI) score. The probability of no response increased with age and BASFI score, and decreased with higher CRP level, BASDAI question 2 score, and PGA. In the testing set (692 participants; mean [SD] age, 38 [11] years; 533 [77.0%] men), models demonstrated moderate to high accuracy. Conclusions and Relevance: In this cohort study, the probability of initial response to TNFi was predicted from baseline variables, which may facilitate personalized treatment decision-making.

Predictive Mechanistic Model of Creep Response of Single-Layered Pressure-Sensitive Adhesive (PSA) Joints.

This paper explores the uniaxial tensile creep response of acrylic-based pressure-sensitive adhesive (PSA), which exhibits a unique multi-phase creep response that does not have the classical steady-state region due to multiple transitions caused by several competing mechanisms: (i) cavity nucleation and growth in the interior of the adhesive material of the PSA system, as well as at the interfaces between the PSA and the substrate; (ii) fibrillation of the bulk adhesive, and (iii) interfacial mechanical locking between the adhesive and the bonding substrate. This results in multiple regimes of strain hardening and strain softening, evidenced by multiple regions of steady-state creep, separated by strong transitions in the creep rates. This complex, multi-phase, nonlinear creep response cannot be described by conventional creep constitutive models commonly used for polymers in commercial finite element codes. Accordingly, based on the empirical uniaxial tensile creep response and the mechanisms behind it, a new mechanistic model was proposed. This is capable of quantitatively capturing the characteristic features of the multiphase creep response of single-layered PSA joints as a function of viscoelastic bulk properties and free energy of the PSA material, substrate surface roughness, and interfacial surface energy between the adhesive and substrate. This is the first paper to present the modeling approach for capturing unique multi-phase creep behavior of PSA joint under tensile loading.

A control theoretic three timescale model for analyzing energy management in mammalian cancer cells.

Interaction among different pathways, such as metabolic, signaling and gene regulatory networks, of cellular system is responsible to maintain homeostasis in a mammalian cell. Malfunctioning of this cooperation may lead to many complex diseases, such as cancer and type 2 diabetes. Timescale differences among these pathways make their integration a daunting task. Metabolic, signaling and gene regulatory networks have three different timescales, such as, ultrafast, fast and slow respectively. The article deals with this problem by developing a support vector regression (SVR) based three timescale model with the application of genetic algorithm based nonlinear controller. The proposed model can successfully capture the nonlinear transient dynamics and regulations of such integrated biochemical pathway under consideration. Besides, the model is quite capable of predicting the effects of certain drug targets for many types of complex diseases. Here, energy and cell proliferation management of mammalian cancer cells have been explored and analyzed with the help of the proposed novel approach. Previous investigations including in silico/in vivo/in vitro experiments have validated the results (the regulations of glucose transporter 1 (glut1), hexokinase (HK), and hypoxia-inducible factor-1 α (HIF-1 α ) among others, and the switching of pyruvate kinase (M2 isoform) between dimer and tetramer) generated by this model proving its effectiveness. Subsequently, the model predicts the effects of six selected drug targets, such as, the deactivation of transketolase and glucose-6-phosphate isomerase among others, in the case of mammalian malignant cells in terms of growth, proliferation, fermentation, and energy supply in the form of adenosine triphosphate (ATP).

Incidence of Hip Fracture Over 4 Decades in the Framingham Heart Study.

Importance: Age-adjusted hip fracture incidence is decreasing in the US. The decrease has been attributed to osteoporosis treatment, but the cause is unknown. Objective: To examine the decrease in hip fracture incidence over the past 40 years in the US. Design, Setting, and Participants: A population-based cohort study using participants in the Framingham Heart Study was conducted. A total of 4918 men and 5634 women were followed up prospectively for the first hip fracture between January 1, 1970, and December 31, 2010. Data were analyzed from May 1, 2019, to May 30, 2020. Main Outcomes and Measures: Incidence of hip fracture and contemporaneous prevalence of risk factors for hip fractures analyzed with age-period-cohort models. Results: The study contained more than 105 000 person-years in 10 552 individuals with a gradual shift toward the offspring participants in the 1980s and 1990s. Women represented more than 55% of the study sample over the years. Adjusted for age, the incidence of hip fracture decreased by 4.4% (95% CI, 6.8%-1.9%) per year from 1970 to 2010. Both period associations (P < .001) and birth cohort associations (P < .001) were statistically significant. For example, in persons aged 85 to 89 years, the incidence of hip fracture was 759 per 100 000 person-years in the offspring group compared with 2018 per 100 000 person-years in the original cohort. The decrease in hip fracture incidence was coincident with a decrease in smoking and heavy drinking. Smoking decreased from 38% in the 1970s to 15% in the late 2000s, while heavy drinking decreased from 7.0% to 4.5%. The prevalence of other risk factors for hip fracture, such as underweight (body mass index <18.5), obesity (body mass index >30), and early menopause (age <45 years) were stable over the study period. When persons who never smoked were evaluated, a change in the incidence of -3.2% (95% CI, -6.0% to -0.4%) per year was observed. The difference between the decrease of the entire population and nonsmokers of 1.5% per year was similar to the hazard ratio conferred by smoking (hazard ratio, 1.5; 95% CI, 1.14-1.96). Conclusions and Relevance: In this study, individuals born more recently appeared to have a low risk for hip fracture. Reductions in smoking and heavy drinking were the risk factor changes coincident with the observed decrease in hip fracture. Attributing the decrease in hip fracture incidence up to 2010 solely to better treatment is not supported by these data, emphasizing the need to treat patients with osteoporosis while continuing to encourage public health interventions for smoking cessation and heavy drinking.

Pre-operative withholding of infliximab and the risk of infections after major surgery in patients with rheumatoid arthritis.

OBJECTIVES: Withholding TNF inhibitors (TNFI) before surgery has been recommended due to concern for post-operative infection. We examined the risks of post-operative infections and mortality in patients with RA in relation to the pre-operative timing of infliximab infusion. METHODS: In this population-based retrospective cohort study, we used US Medicare claims data from 2007 to 2015 to identify patients with RA who underwent coronary artery bypass grafting (CABG), aortic or vascular surgery, or bowel resection, and who were treated with infliximab in the 90 days prior to surgery. We examined associations between the timing of infusion and infections and mortality in the 30 days after surgery. We adjusted for the predicted probability of post-operative infection or death, demographic characteristics, use of MTX, post-operative blood transfusion and hospital volume. RESULTS: We studied 712 patients with CABG, 244 patients with vascular surgery and 862 patients with bowel resections. Post-operative pneumonia occurred in 7.4-11.9%, urinary tract infection in 9.0-15.2%, surgical site infection in 3.2-18.9%, sepsis in 4.2-9.6% and death in 3.5-7.0% among surgery cohorts. There was no association between the time from last infliximab dose to surgery and the risk of post-operative infection or mortality in any surgical cohort. No subgroups were identified that had an increased risk of infection with more proximate use of infliximab. CONCLUSION: Among elderly patients with RA, risks of infection and mortality after major surgery were not related to the pre-operative timing of infliximab infusion.

Racial/Ethnic Differences in Dialysis Discontinuation and Survival after Hospitalization for Serious Conditions among Patients on Maintenance Dialysis.

BACKGROUND: Racial and ethnic minorities on dialysis survive longer than whites, and are less likely to discontinue dialysis. Both differences have been attributed by some clinicians to better health among minorities on dialysis. METHODS: To test if racial and ethnic differences in dialysis discontinuation reflected better health, we conducted a retrospective cohort study of survival and dialysis discontinuation among patients on maintenance dialysis in the US Renal Data System after hospitalization for either stroke (n=60,734), lung cancer (n=4100), dementia (n=40,084), or failure to thrive (n=42,950) between 2003 and 2014. We examined the frequency of discontinuation of dialysis and used simulations to estimate survival in minorities relative to whites if minorities had the same pattern of dialysis discontinuation as whites. RESULTS: Blacks, Hispanics, and Asians had substantially lower frequencies of dialysis discontinuation than whites in each hospitalization cohort. Observed risks of mortality were also lower for blacks, Hispanics, and Asians. In simulations that assigned discontinuation patterns similar to those found among whites across racial and ethnic groups, differences in survival were markedly attenuated and hazard ratios approached 1.0. Survival and dialysis discontinuation frequencies among American Indians and Alaska Natives were close to those of whites. CONCLUSIONS: Racial and ethnic differences in dialysis discontinuation were present among patients hospitalized with similar health events. Among these patients, survival differences between racial and ethnic minorities and whites were largely attributable to differences in the frequency of discontinuation of dialysis.

Succinate aggravates NAFLD progression to liver cancer on the onset of obesity: An in silico model.

The incidence and prevalence of nonalcoholic fatty liver disease (NAFLD) have been increasing to epidemic proportions around the world. NAFLD, a chronic liver disease that affects the nondrinkers, is mainly associated with steatohepatitis and cirrhosis. The progression of NAFLD associated with obesity increases the risk of liver cancer, a disease with poor outcomes and limited therapeutic options. In order to investigate the underlying cellular dynamics leading to NAFLD progression towards cancer on the onset of obesity, we have integrated human hepatocyte pathway with hypoxia-inducible factor1- α (HIF1- α ) signaling pathway using state space model based on classical control theory. Modified Michaelis-Menten equation and mass action law have been used to define flux vectors of the proposed model. We have incorporated feedback inhibition/activation and allosteric effects into the simulink-based model. The values of kinetic constants have been taken from the literature. It is found that on the onset of obesity, HIF1- α -induced proteins stabilize approximately 62 times that in the case of a normal cell. Consequently, the HIF1- α -induced proteins enhance the enzymatic activities of hexokinase (HK), phosphofructo kinase (PFK), lactate dehydrogenase (LDH), and pyruvate dehydrogenase (PDH), which induce Warburg effect promoting an environment suitable for cancer cells.

Comparative Efficacy of Tumor Necrosis Factor-α Inhibitors in Ankylosing Spondylitis: A Systematic Review and Bayesian Network Metaanalysis.

OBJECTIVE: To compare the efficacy of 6 tumor necrosis factor-α inhibitors (TNFi) in treatment of ankylosing spondylitis (AS) at 12 weeks and 24 weeks. METHODS: We performed a systematic literature review of randomized controlled trials of TNFi in patients with active AS. We included trials that reported efficacy at 10 to 14 weeks (12-week analysis) and at 24 to 30 weeks (24-week analysis). We used Bayesian network metaanalysis (NMA) to compare their relative efficacy to improve the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Bath Ankylosing Spondylitis Functional Index (BASFI), and C-reactive protein (CRP) level. RESULTS: We included 20 trials of 6 TNFi, with 43 treatment arms and 3220 participants. All TNFi were significantly better than placebo in reducing BASDAI and BASFI at 12 weeks and 24 weeks; all but certolizumab pegol (CZP) were statistically better than placebo in reducing CRP at 12 weeks; all but CZP and infliximab-dyyb (IFX biosimilar) were significantly better than placebo in reducing CRP at 24 weeks. IFX was superior to the other TNFi in decreasing BASDAI at 12 weeks, but not at 24 weeks. Excluding 1 open-label trial, there were no differences among TNFi. CONCLUSION: Based on this NMA of clinical trials, IFX was superior to other TNFi in reducing BASDAI at 12 weeks, but sensitive to inclusion of an open-label trial, and its efficacy was diminished at 24 weeks. The analysis was limited by few direct comparison trials. Further study of relative safety and longterm effectiveness will help inform the choice of TNFi in treating active AS.

Trend Toward High-Volume Hospitals and the Influence on Complications in Knee and Hip Arthroplasty.

BACKGROUND: Hospitals in which a high volume of arthroplasty procedures are performed have been observed to have better outcomes. As the number of arthroplasties has increased, it is not known whether surgical cases have shifted to high-volume hospitals. In this study, we examined the change in the volume of arthroplasties to provide a contemporary definition of "high-volume" centers, quantified surgical volume that shifted to high-volume centers, and investigated the resulting effect on complications. METHODS: Data from the National (Nationwide) Inpatient Sample (2000 to 2012) were used to quantify trends in total hip arthroplasty (THA) and total knee arthroplasty (TKA) volume. Elective primary THAs and TKAs were identified and grouped by hospital by utilizing the hospital identifier, which indicates the geographic location of the hospital. County geographic and population data were obtained from the U.S. Census, and the distances between hospitals and the centroids of counties were calculated. Risk-standardized surgical complication rates for hospitals (2009 to 2012) were obtained from Medicare Hospital Compare and grouped by hospital volume. RESULTS: From 2000 to 2012, there was a marked increase in the number of hospitals that performed a combined volume of ≥400 elective primary THAs and TKAs. The number of elective primary TKAs and THAs performed annually increased from 343,000 to 851,000. In 2012, 65.5% of the arthroplasties were performed in high-volume hospitals (≥400 arthroplasties annually), and 26.6% of the arthroplasties were performed in very high-volume hospitals (≥1,000 procedures annually). The proportion of arthroplasties performed in low-volume hospitals (<100 arthroplasties annually) shrank from 17.9% to 5.4%. Very high-volume hospitals had the lowest complication rates (2.745 per 100; 95% confidence interval [CI], 2.56 to 2.93), and low-volume hospitals had the highest complication rates (3.610 per 100; 95% CI, 3.58 to 3.64; p < 0.0001) (odds ratio, 1.327; 95% CI, 1.26 to 1.40). Our analysis showed that 81.9% of the U.S. population lived within 50 miles of a high-volume hospital. CONCLUSIONS: Arthroplasty patients are electing to have their procedures at higher-volume hospitals in the United States. Each successively higher hospital volume category manifested a lower complication rate.

A fuzzy logic controller based approach to model the switching mechanism of the mammalian central carbon metabolic pathway in normal and cancer cells.

Dynamics of large nonlinear complex systems, like metabolic networks, depend on several parameters. A metabolic pathway may switch to another pathway in accordance with the current state of parameters in both normal and cancer cells. Here, most of the parameter values are unknown to us. A fuzzy logic controller (FLC) has been developed here for the purpose of modeling metabolic networks by approximating the reasons for the behaviour of a system and applying expert knowledge to track switching between metabolic pathways. The simulation results can track the switching between glycolysis and gluconeogenesis, as well as glycolysis and pentose phosphate pathways (PPP) in normal cells. Unlike normal cells, pyruvate kinase (M2 isoform) (PKM2) switches alternatively between its two oligomeric forms, i.e. an active tetramer and a relatively low activity dimer, in cancer cells. Besides, there is a coordination among PKM2 switching and enzymes catalyzing PPP. These phenomena help cancer cells to maintain their high energy demand and macromolecular synthesis. However, the reduction of initial adenosine triphosphate (ATP) to a very low concentration, decreasing initial glucose uptake, destroying coordination between glycolysis and PPP, and replacement of PKM2 by its relatively inactive oligomeric form (dimer) or inhibition of the translation of PKM2 may destabilize the mutated control mechanism of the mammalian central carbon metabolic (CCM) pathway in cancer cells. The performance of the model is compared appropriately with some existing ones.

Exploring the Altered Dynamics of Mammalian Central Carbon Metabolic Pathway in Cancer Cells: A Classical Control Theoretic Approach.

BACKGROUND: In contrast with normal cells, most of the cancer cells depend on aerobic glycolysis for energy production in the form of adenosine triphosphate (ATP) bypassing mitochondrial oxidative phosphorylation. Moreover, compared to normal cells, cancer cells exhibit higher consumption of glucose with higher production of lactate. Again, higher rate of glycolysis provides the necessary glycolytic intermediary precursors for DNA, protein and lipid synthesis to maintain high active proliferation of the tumor cells. In this scenario, classical control theory based approach may be useful to explore the altered dynamics of the cancer cells. Since the dynamics of the cancer cells is different from that of the normal cells, understanding their dynamics may lead to development of novel therapeutic strategies. METHOD: We have developed a model based on the state space equations of classical control theory along with an order reduction technique to mimic the actual dynamic behavior of mammalian central carbon metabolic (CCM) pathway in normal cells. Here, we have modified Michaelis Menten kinetic equation to incorporate feedback mechanism along with perturbations and cross talks associated with a metabolic pathway. Furthermore, we have perturbed the proposed model to reduce the mitochondrial oxidative phosphorylation. Thereafter, we have connected proportional-integral (PI) controller(s) with the model for tuning it to behave like the CCM pathway of a cancer cell. This methodology allows one to track the altered dynamics mediated by different enzymes. RESULTS AND DISCUSSIONS: The proposed model successfully mimics all the probable dynamics of the CCM pathway in normal cells. Moreover, experimental results demonstrate that in cancer cells, a coordination among enzymes catalyzing pentose phosphate pathway and intermediate glycolytic enzymes along with switching of pyruvate kinase (M2 isoform) plays an important role to maintain their altered dynamics.

Using the "reverse Warburg effect" to identify high-risk breast cancer patients: stromal MCT4 predicts poor clinical outcome in triple-negative breast cancers.

We have recently proposed a new model of cancer metabolism to explain the role of aerobic glycolysis and L-lactate production in fueling tumor growth and metastasis. In this model, cancer cells secrete hydrogen peroxide (H2O2), initiating oxidative stress and aerobic glycolysis in the tumor stroma. This, in turn, drives L-lactate secretion from cancer-associated fibroblasts. Secreted L-lactate then fuels oxidative mitochondrial metabolism (OXPHOS) in epithelial cancer cells, by acting as a paracrine onco-metabolite. We have previously termed this type of two-compartment tumor metabolism the "Reverse Warburg Effect," as aerobic glycolysis takes place in stromal fibroblasts, rather than epithelial cancer cells. Here, we used MCT4 immuno-staining of human breast cancer tissue microarrays (TMAs; > 180 triple-negative patients) to directly assess the prognostic value of the "Reverse Warburg Effect." MCT4 expression is a functional marker of hypoxia, oxidative stress, aerobic glycolysis, and L-lactate efflux. Remarkably, high stromal MCT4 levels (score = 2) were specifically associated with decreased overall survival (< 18% survival at 10 y post-diagnosis). In contrast, patients with absent stromal MCT4 expression (score = 0), had 10-y survival rates of ~97% (p-value < 10 (-32) ). High stromal levels of MCT4 were strictly correlated with a loss of stromal Cav-1 (p-value < 10 (-14) ), a known marker of early tumor recurrence and metastasis. In fact, the combined use of stromal Cav-1 and stromal MCT4 allowed us to more precisely identify high-risk triple-negative breast cancer patients, consistent with the goal of individualized risk-assessment and personalized cancer treatment. However, epithelial MCT4 staining had no prognostic value, indicating that the "conventional" Warburg effect does not predict clinical outcome. Thus, the "Reverse Warburg Effect" or "parasitic" energy-transfer is a key determinant of poor overall patient survival. As MCT4 is a druggable-target, MCT4 inhibitors should be developed for the treatment of aggressive breast cancers, and possibly other types of human cancers. Similarly, we discuss how stromal MCT4 could be used as a biomarker for identifying high-risk cancer patients that could likely benefit from treatment with FDA-approved drugs or existing MCT-inhibitors (such as, AR-C155858, AR-C117977, and AZD-3965).

Suicidal ideation among adults with arthritis: prevalence and subgroups at highest risk. Data from the 2007-2008 National Health and Nutrition Examination Survey.

OBJECTIVE: To evaluate the prevalence, correlates, and subgroups at highest risk for suicidal ideation among adults with arthritis. METHODS: We used data on US adults with arthritis, ages ≥40 years, participating in the 2007-2008 National Health and Nutrition Examination Survey. Suicidal ideation was assessed by item 9 of the Patient Health Questionnaire 9 (PHQ-9). Sociodemographic factors, health behaviors, and comorbid conditions were examined as potential correlates. Depression was measured by the PHQ-8 score (range 1-24). We used random forests to identify subgroups at highest risk for suicidal ideation. To determine if any correlates were unique to arthritis, we compared results to those for persons with diabetes mellitus and cancer. RESULTS: The prevalence ± SEM of suicidal ideation was 5.6% ± 0.8% among persons with arthritis and 2.4% ± 0.4% among those without. The most important correlates for suicidal ideation in adults with arthritis were depression, anxiety, duration of arthritis, age, income:poverty ratio, number of close friends, pain, alcohol, excessive daytime sleepiness, and comorbidities. Eleven of the 16 most important contributors for suicidal ideation among adults with arthritis were also important for people with diabetes mellitus and cancer. Among persons with arthritis, subgroups at highest risk for suicidal ideation were those with a PHQ-8 score between 18 and 24 and less than 4.5 years of arthritis (96.5%), and those with a PHQ-8 score between 7 and 17, ≥1.24 days of binges/month, and either an income of ≥$45,000/year (85.4%) or an income of <$45,000/year and >3 comorbidities (70.8%). CONCLUSION: Depression, short duration of arthritis, binge drinking, income, and >3 comorbidities identified subgroups of adults with arthritis at greatest risk for suicidal ideation.

pp32 (ANP32A) expression inhibits pancreatic cancer cell growth and induces gemcitabine resistance by disrupting HuR binding to mRNAs.

The expression of protein phosphatase 32 (PP32, ANP32A) is low in poorly differentiated pancreatic cancers and is linked to the levels of HuR (ELAV1), a predictive marker for gemcitabine response. In pancreatic cancer cells, exogenous overexpression of pp32 inhibited cell growth, supporting its long-recognized role as a tumor suppressor in pancreatic cancer. In chemotherapeutic sensitivity screening assays, cells overexpressing pp32 were selectively resistant to the nucleoside analogs gemcitabine and cytarabine (ARA-C), but were sensitized to 5-fluorouracil; conversely, silencing pp32 in pancreatic cancer cells enhanced gemcitabine sensitivity. The cytoplasmic levels of pp32 increased after cancer cells are treated with certain stressors, including gemcitabine. pp32 overexpression reduced the association of HuR with the mRNA encoding the gemcitabine-metabolizing enzyme deoxycytidine kinase (dCK), causing a significant reduction in dCK protein levels. Similarly, ectopic pp32 expression caused a reduction in HuR binding of mRNAs encoding tumor-promoting proteins (e.g., VEGF and HuR), while silencing pp32 dramatically enhanced the binding of these mRNA targets. Low pp32 nuclear expression correlated with high-grade tumors and the presence of lymph node metastasis, as compared to patients' tumors with high nuclear pp32 expression. Although pp32 expression levels did not enhance the predictive power of cytoplasmic HuR status, nuclear pp32 levels and cytoplasmic HuR levels associated significantly in patient samples. Thus, we provide novel evidence that the tumor suppressor function of pp32 can be attributed to its ability to disrupt HuR binding to target mRNAs encoding key proteins for cancer cell survival and drug efficacy.

Skeletal muscle involvement in human immunodeficiency virus infection: a report of four cases.

Human immunodeficiency virus (HIV) may affect any part of the neuraxis and may affect skeletal muscle in many ways, ranging from myofiber atrophy in the wasting syndrome to inflammatory muscle disease and a host of opportunistic infections involving muscle. We report here a case series of 4 zidovudine-naοve patients with proven HIV infection with myopathy. One was a case of HIV wasting syndrome, and the three others were diagnosed as HIV polymyositis. Muscle biopsy proved invaluable in the characterization of these cases.

Implications of enhancer of zeste homologue 2 expression in pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma is the fourth leading cause of cancer deaths in the United States. Single-agent gemcitabine remains the standard treatment of advanced pancreatic adenocarcinoma. A recently discovered histone methyltransferase termed enhancer of zeste homologue 2 (EZH2) was found to be overexpressed in a variety of carcinomas including pancreatic adenocarcinoma. Silencing of E-cadherin was proposed as a mechanism by which enhancer of zeste homologue 2 mediates tumor aggressiveness, and enhancer of zeste homologue 2 depletion has been found to sensitize pancreatic cancer cells to gemcitabine. In this study, we correlated enhancer of zeste homologue 2 with E-cadherin expression in pancreatic adenocarcinoma and evaluated response to gemcitabine in relation to enhancer of zeste homologue 2 expression in tumor cells. Fifty-four pancreatic adenocarcinomas, 13 intraductal papillary mucinous neoplasms, and 6 chronic pancreatitis cases were stained with antibodies against enhancer of zeste homologue 2 and E-cadherin. Enhancer of zeste homologue 2 staining was scored from 1 to 4+ and classified as either low (1-2+ in <25% of tumor nuclei) or high (3-4+ in >25% of tumor nuclei). E-cadherin expression was scored on membrane positivity as follows: 0 (0%-10%), 1 (10%-25%), 2 (25%-75%), and 3 (>75%). High enhancer of zeste homologue 2 expression in pancreatic adenocarcinoma was significantly associated with decreased E-cadherin expression and more aggressive disease. There was significantly longer survival in gemcitabine-treated patients with low versus high enhancer of zeste homologue 2 expression. High enhancer of zeste homologue 2 expression was detected in intraductal papillary mucinous neoplasms with moderate to severe dysplasia, but not in chronic pancreatitis. Our study suggests that E-cadherin down-regulation may lead to enhancer of zeste homologue 2-mediated invasion and metastasis.

Dynamic changes in lymphocyte GRK2 levels in cardiac transplant patients: a biomarker for left ventricular function.

G protein-coupled receptor kinase 2 (GRK2), which is upregulated in the failing human myocardium, appears to have a role in heart failure (HF) pathogenesis. In peripheral lymphocytes, GRK2 expression has been shown to reflect myocardial levels. This study represents an attempt to define the role for GRK2 as a potential biomarker of left ventricular function in HF patients. We obtained blood from 24 HF patients before and after heart transplantation and followed them for up to 1 year, also recording hemodynamic data and histological results from endomyocardial biopsies. We determined blood GRK2 protein by Western blotting and enzyme-linked immunosorbent assay. GRK2 levels were obtained before transplant and at first posttransplant biopsy. GRK2 levels significantly declined after transplant and remained low over the course of the study period. After transplantation, we found that blood GRK2 significantly dropped and remained low consistent with improved cardiac function in the transplanted heart. Blood GRK2 has potential as a biomarker for myocardial function in end-stage HF.

Loss of stromal caveolin-1 expression predicts poor clinical outcome in triple negative and basal-like breast cancers.

Here, we investigated the possible predictive value of stromal caveolin-1 (Cav-1) as a candidate biomarker for clinical outcome in triple negative (TN) breast cancer patients. A cohort of 85 TN breast cancer patients was available, with the necessary annotation and nearly 12 years of follow-up data. Our primary outcome of interest in this study was overall survival. Interestingly, TN patients with high-levels of stromal Cav-1 had a good clinical outcome, with >50% of the patients remaining alive during the follow-up period. In contrast, the median survival for TN patients with moderate stromal Cav-1 staining was 33.5 months. Similarly, the median survival for TN patients with absent stromal Cav-1 staining was 25.7 months. A comparison of 5-year survival rates yields a similar pattern. TN patients with high stromal Cav-1 had a good 5-year survival rate, with 75.5% of the patients remaining alive. In contrast, TN patients with moderate or absent stromal Cav-1 levels had progressively worse 5-year survival rates, with 40 and 9.4% of the patients remaining alive. In contrast, in a parallel analysis, the levels of tumor epithelial Cav-1 had no prognostic significance. As such, the prognostic value of Cav-1 immunostaining in TN breast cancer patients is compartment-specific, and selective for an absence of Cav-1 staining in the stromal fibroblast compartment. A recursive-partitioning algorithm was used to assess which factors are most predictive of overall survival in TN breast cancer patients. In this analysis, we included tumor size, histologic grade, whether the patient received surgery, radiotherapy or chemotherapy, CK5/6, EGFR, p53 and Ki67 status, as well as the stromal Cav-1 score. This analysis indicated that stromal loss of Cav-1 expression was the most important prognostic factor for overall survival in TN breast cancer. Virtually identical results were obtained with CK5/6 (+) and/or EGFR (+) TN breast cancer cases, demonstrating that a loss of stromal Cav-1 is also a strong prognostic factor for basal-like breast cancers. Our current findings may have important implications for the close monitoring and treatment stratification of TN and basal-like breast cancer patients.