Modeling development using hydrogels.

The development of multicellular complex organisms relies on coordinated signaling from the microenvironment, including both biochemical and mechanical interactions. To better understand developmental biology, increasingly sophisticated in vitro systems are needed to mimic these complex extracellular features. In this Primer, we explore how engineered hydrogels can serve as in vitro culture platforms to present such signals in a controlled manner and include examples of how they have been used to advance our understanding of developmental biology.

18F-fluciclovine-PET/CT imaging versus conventional imaging alone to guide postprostatectomy salvage radiotherapy for prostate cancer (EMPIRE-1): a single centre, open-label, phase 2/3 randomised controlled trial.

BACKGROUND: Molecular imaging is increasingly used to guide treatment decisions and planning in prostate cancer. We aimed to evaluate the role of 18F-fluciclovine-PET/CT in improving cancer control compared with conventional imaging (bone scan and either CT or MRI) alone for salvage postprostatectomy radiotherapy. METHODS: In EMPIRE-1, a single-centre, open-label, phase 2/3 randomised controlled trial, patients with prostate cancer with detectable PSA after prostatectomy and negative conventional imaging (no extrapelvic or bone findings) were randomly assigned in a 1:1 ratio to radiotherapy directed by conventional imaging alone or to conventional imaging plus 18F-fluciclovine-PET/CT. Computer-generated randomisation was stratified by PSA concentration, adverse pathology indicators, and androgen deprivation therapy intent. In the 18F-fluciclovine-PET/CT group, radiotherapy decisions were rigidly determined by PET findings, which were also used for target delineation. The primary endpoint was 3 year event-free survival, with events defined as biochemical or clinical recurrence or progression, or initiation of systemic therapy, using univariate and multivariable analyses in patients who received radiotherapy. This trial is registered with ClinicalTrials.gov, NCT01666808 and is closed to new participants. FINDINGS: From Sept 18, 2012, to March 4, 2019, 165 patients were randomly assigned, with median follow-up of 3·52 years (95% CI 2·98-3·95). PET findings resulted in four patients in the 18F-fluciclovine-PET/CT group having radiotherapy aborted; these patients were excluded from survival analyses. Median survival was not reached (95% CI 35·2-not reached; 33% of 81 patients had events) in the conventional imaging group compared with not reached (95% CI not reached-not reached; 20% of 76 patients) in the 18F-fluciclovine-PET/CT group, and 3 year event-free survival was 63·0% (95% CI 49·2-74·0) in the conventional imaging group versus 75·5% (95% CI 62·5-84·6) for 18F-fluciclovine-PET/CT (difference 12·5; 95% CI 4·3-20·8; p=0·0028). In adjusted analyses, study group (hazard ratio 2·04 [95% CI 1·06-3·93], p=0·0327) was significantly associated with event-free survival. Toxicity was similar in both study groups, with the most common adverse events being late urinary frequency or urgency (37 [46%] of 81 patients in the conventional imaging group and 31 [41%] of 76 in the PET group), and acute diarrhoea (11 [14%] in the conventional imaging group and 16 [21%] in the PET group). INTERPRETATION: Inclusion of 18F-fluciclovine-PET into postprostatectomy radiotherapy decision making and planning significantly improved survival free from biochemical recurrence or persistence. Integration of novel PET radiotracers into radiotherapy decisions and planning for prostate cancer patients warrants further study. FUNDING: National Institutes of Health/National Cancer Institute, Blue Earth Diagnostics, and Winship Cancer Institute of Emory University.

Effect of immunotherapy time-of-day infusion on overall survival among patients with advanced melanoma in the USA (MEMOIR): a propensity score-matched analysis of a single-centre, longitudinal study.

BACKGROUND: The dependence of the adaptive immune system on circadian rhythm is an emerging field of study with potential therapeutic implications. We aimed to determine whether specific time-of-day patterns of immune checkpoint inhibitor infusions might alter melanoma treatment efficacy. METHODS: Melanoma Outcomes Following Immunotherapy (MEMOIR) is a longitudinal study of all patients with melanoma who received ipilimumab, nivolumab, or pembrolizumab, or a combination of these at a single tertiary cancer centre (Winship Cancer Institute of Emory University, Atlanta, GA, USA). For this analysis, we collected deidentified participant-level data from the MEMOIR database for adults (age ≥18 years) diagnosed with stage IV melanoma between 2012 and 2020. Those who received fewer than four infusions were excluded. Standard of care doses were used, with modifications at the treating physicians' discretion. The primary outcome was overall survival, defined as death from any cause and indexed from date of first infusion of immune checkpoint inhibitor. We calculated the association between overall survival and proportion of infusions of immune checkpoint inhibitors received after 1630 h (a composite time cutoff derived from seminal studies of the immune-circadian rhythm to represent onset of evening) using Cox regression and propensity score-matching on age, Eastern Cooperative Oncology Group performance status, serum lactate dehydrogenase concentration, and receipt of corticosteroids and radiotherapy. Treatment-related adverse events that led to change or discontinuation of immune checkpoint inhibitors were also assessed. FINDINGS: Between Jan 1, 2012, and Dec 31, 2020, 481 patients with melanoma received treatment with immune checkpoint inhibitors at the study centre, of whom 299 had stage IV disease and were included in this study; median follow-up was 27 months (IQR 14 to 47). In the complete unmatched sample, 102 (34%) patients were female and 197 (66%) were male, with a median age of 61 years (IQR 51 to 72). Every additional 20% of infusions of immune checkpoint inhibitors received after 1630 h (among all infusions received by a patient) conferred an overall survival hazard ratio (HR) of 1·31 (95% CI 1·00 to 1·71; p=0·046). A propensity score-matched analysis of patients who did (n=73) and did not (n=73) receive at least 20% of their infusions of immune checkpoint inhibitors after 1630 h (54 [37%] of 146 patients were women and 92 [63%] were men, with a median age of 58 years [IQR 48 to 68]) showed that having at least 20% of infusions in the evening was associated with shorter overall survival (median 4·8 years [95% CI 3·9 to not estimable] vs not reached; HR 2·04 [1·04 to 4·00; p=0·038]). This result remained robust to multivariable proportional hazards adjustment with (HR 1·80 [1·08 to 2·98; p=0·023]) and without (2·16 [1·10 to 4·25; p=0·025]) inclusion of the complete unmatched study sample. The most common adverse events were colitis (54 [18%] of 299 patients), hepatitis (27 [9%]), and hypophysitis (15 [5%]), and there were no treatment-related deaths. INTERPRETATION: Our findings are in line with an increasing body of evidence that adaptive immune responses are less robust when initially stimulated in the evening than if stimulated in the daytime. Although prospective studies of the timing of immune checkpoint inhibitor infusions are warranted, efforts towards scheduling infusions before mid-afternoon could be considered in the multidisciplinary management of advanced melanoma. FUNDING: National Institutes of Health, American Society for Radiation Oncology and Melanoma Research Alliance, and Winship Cancer Institute.

Survival outcomes in patients with gastric and gastroesophageal junction adenocarcinomas treated with perioperative chemotherapy with or without preoperative radiotherapy.

BACKGROUND: Perioperative chemotherapy (POC) is one standard approach for the treatment of resectable cancers of the stomach and gastroesophageal junction (GEJ), whereas there has been growing interest in preoperative therapies. The objective of the current study was to compare survival between patients treated with preoperative chemoradiotherapy and adjuvant chemotherapy (PCRT) with those receiving POC using a large database. METHODS: The National Cancer Data Base was queried for patients diagnosed between 2004 and 2013 with American Joint Committee on Cancer clinical group stage IB to stage IIIC (excluding T2N0 disease) adenocarcinoma of the stomach or GEJ. Patients treated with definitive surgery and POC with or without preoperative radiotherapy of 41 to 54 Gy were included. Overall survival (OS) was defined from the date of definitive surgery and estimated using the Kaplan-Meier method. A total of 14 patient and treatment variables were used for propensity score matching (PSM). RESULTS: A total of 1048 patients were analyzed: 53.2% received POC and 46.8% received PCRT. The primary tumor site was the GEJ in 69.1% of patients and stomach in 30.9% of patients. The median age of the patients was 60 years, and the median follow-up was 25.8 months. The use of PCRT was associated with a greater pathologic complete response rate of 13.1% versus 8.2% (P = .01). POC was associated with a decreased risk of death in unmatched groups (hazard ratio [HR], 0.83; P = .043). Using PSM cohorts, POC decreased the risk of death with a median OS of 45.1 months versus 31.4 months (HR, 0.70; P = .016). The 2-year OS rate was 72.9% versus 62.5% and the 5-year OS rate was 40.7% versus 33.1% for POC versus PCRT, respectively. Survival favored POC in PSM gastric (HR, 0.41; P = .07) and GEJ (HR, 0.77; P = .08) patient subgroups. CONCLUSIONS: The addition of preoperative radiotherapy to POC appears to be associated with an increased risk of death in patients with resectable gastric and GEJ cancers.

A Calibrated Method of Massage Therapy Decreases Systolic Blood Pressure Concomitant With Changes in Heart Rate Variability in Male Rats.

OBJECTIVE: The purpose of this study was to develop a method for applying calibrated manual massage pressures by using commonly available, inexpensive sphygmomanometer parts and validate the use of this approach as a quantitative method of applying massage therapy to rodents. METHODS: Massage pressures were monitored by using a modified neonatal blood pressure (BP) cuff attached to an aneroid gauge. Lightly anesthetized rats were stroked on the ventral abdomen for 5 minutes at pressures of 20 mm Hg and 40 mm Hg. Blood pressure was monitored noninvasively for 20 minutes following massage therapy at 5-minute intervals. Interexaminer reliability was assessed by applying 20 mm Hg and 40 mm Hg pressures to a digital scale in the presence or absence of the pressure gauge. RESULTS: With the use of this method, we observed good interexaminer reliability, with intraclass coefficients of 0.989 versus 0.624 in blinded controls. In Long-Evans rats, systolic BP dropped by an average of 9.86% ± 0.27% following application of 40 mm Hg massage pressure. Similar effects were seen following 20 mm Hg pressure (6.52% ± 1.7%), although latency to effect was greater than at 40 mm Hg. Sprague-Dawley rats behaved similarly to Long-Evans rats. Low-frequency/high-frequency ratio, a widely-used index of autonomic tone in cardiovascular regulation, showed a significant increase within 5 minutes after 40 mm Hg massage pressure was applied. CONCLUSIONS: The calibrated massage method was shown to be a reproducible method for applying massage pressures in rodents and lowering BP.

Pharmacogenomic incidental findings in 308 families: The NIH Undiagnosed Diseases Program experience.

PURPOSE: Using single-nucleotide polymorphism (SNP) chip and exome sequence data from individuals participating in the National Institutes of Health (NIH) Undiagnosed Diseases Program (UDP), we evaluated the number and therapeutic informativeness of incidental pharmacogenetic variants. METHODS: Pharmacogenomics Knowledgebase (PharmGKB) annotated sequence variants were identified in 1,101 individuals. Medication records of participants were used to identify individuals prescribed medications with a genetic variant that might alter efficacy. RESULTS: A total of 395 sequence variants, including 19 PharmGKB 1A and 1B variants, were identified in SNP chip sequence data, and 388 variants, including 21 PharmGKB 1A and 1B variants, were identified in the exome sequence data. Nine participants had incidental pharmacogenetic variants associated with altered efficacy of a prescribed medication. CONCLUSIONS: Despite the small size of the NIH UDP patient cohort, we identified pharmacogenetic incidental findings potentially useful for guiding therapy. Consequently, groups conducting clinical genomic studies might consider reporting of pharmacogenetic incidental findings.Genet Med 18 12, 1303-1307.

Occurrence, Distribution, and Accumulation of Pesticides in Exterior Residential Areas.

Pesticides are commonly applied around residential homes, but their occurrence on exterior surfaces (e.g., pavement) has not been thoroughly evaluated. We collected 360 dust samples from curbside gutters, sidewalks, and street surfaces at 40 houses in southern California to evaluate pesticide occurrence on urban paved surfaces as well as their spatial and temporal distributions. Pesticides and select degradates were ubiquitously detected in dust, with the median concentration of total target analytes at 85 µg kg-1. A total of 75% of samples contained at least five pesticides. As a result of recurring pesticide applications, concentrations increased throughout the summer. The pyrethroids bifenthrin and permethrin accounted for 55% of total pesticides detected in the dust. The highest concentrations in dust were found on the sidewalk and in the gutter. Relative to indoor environments, human exposure risk to pesticides on paved surfaces was estimated to be lower, with the highest potential oral and dermal exposure predicted to be 38 ng day-1 for permethrin. The ubiquitous detection of pesticides on residential outdoor surfaces and the fact that the exterior concentrations did not correlate to the indoor areas highlight the necessity to measure pesticides in both indoor and outdoor areas for complete residential pesticide risk assessment.

Utilization and Role of Adjuvant Radiotherapy and Chemotherapy for Uterine Clear Cell Carcinoma: A National Cancer Data Base Analysis.

OBJECTIVE: Because of the rarity of uterine clear cell carcinoma (UCCC), a National Cancer Data Base analysis was conducted to evaluate practice patterns and implications of adjuvant therapy. METHODS: The National Cancer Data Base was queried for UCCC patients diagnosed from 1998 to 2011. Patients receiving neoadjuvant therapy, lacking surgical staging, or having follow-up time shorter than 6 months were excluded. Factors associated with utilization were assessed using logistic regression. To define the probability of receiving chemotherapy and radiotherapy (CT + RT), propensity scores with inverse probability of treatment weighting (IPTW) were calculated using multivariable logistic regression. Log-rank test and multivariable IPTW-adjusted Cox proportional hazards modeling were then conducted. RESULTS: A total of 2504 patients were identified, with a median follow-up of 65.5 months. Most patients had FIGO (International Federation of Gynecology and Obstetrics) stage I to II UCCC (71.4%). Adjuvant RT alone, CT alone, or CT + RT was given in 35.3%, 9.5%, and 11.7%, respectively. Among those receiving RT, external beam was the most common modality (69.4%). Later year of diagnosis (>2005: odds ratio [OR], 4.42; 95% confidence interval [95% CI], 2.44-8.01), higher FIGO stage (IIIA-IIIC2: OR, 6.34; 95% CI, 3.93-10.24), larger tumor size (3.6-5.0 cm: OR, 3.40; 95% CI, 1.76-6.55), and lymph node dissection (OR, 4.22; 95% CI, 1.60-11.15) were associated with a higher chance of receiving CT + RT. With IPTW-adjusted multivariable analysis, CT + RT significantly decreased mortality risk in stage III to IVA patients (hazards ratio, 0.41; 95% CI, 0.22-0.77), trending toward benefit in stage I to II patients (hazards ratio, 0.53; 95% CI, 0.27-1.07). CONCLUSIONS: In this hospital-based registry analysis of UCCC, adjuvant CT + RT significantly reduced the risk of death, reaching statistical significance for stage III to IVA patients.

Adoption and impact of concurrent chemoradiation therapy for vaginal cancer: a National Cancer Data Base (NCDB) study.

BACKGROUND: Vaginal cancer is an uncommon entity for which concurrent chemoradiation (CCRT) may be used based on small retrospective series and extrapolation from cervical cancer. We explored the adoption rate of CCRT and determined its impact on survival. METHODS: Patients entered into the National Cancer Data Base (NCDB) diagnosed with vaginal cancer from 1998 to 2011 who received definitive radiation therapy were included. Univariate/multivariable exploratory analyses of factors associated with CCRT were performed. Log-rank test and Cox proportional hazards modeling identified the contribution of CCRT on survival. RESULTS: Of the 13,689 patients identified, 8222 (60.1%) received radiation therapy. Of these, 3932 (47.8%) received CCRT and its use increased from 20.8% to 59.1% (1998-2011). Of the 23 patient, disease, facility, and treatment factors, 13 were significantly associated with patient outcomes and were entered into a binary logistic regression model. This evaluation revealed that younger age, larger tumor size, later year of diagnosis, higher facility volume, squamous histology, and higher stage (in order of increasing association) are independently associated with CCRT use. Median overall survival is longer with CCRT compared to radiation alone (56.2 vs. 41.2 months, p<0.0005). On multivariable analysis, younger age, higher facility volume, squamous histology, lower comorbidity score, CCRT, brachytherapy utilization and lower stage (in order of increasing association) are independently prognostic of improved survival. CONCLUSIONS: Use of CCRT for patients with vaginal cancer has increased and is associated with a significant improvement in survival in this large, national cohort. CCRT should be integrated into treatment guidelines for vaginal cancer.

Local and Sustained Baricitinib Delivery to the Skin through Injectable Hydrogels Containing Reversible Thioimidate Adducts.

Janus kinase (JAK) inhibitors are approved for many dermatologic disorders, but their use is limited by systemic toxicities including serious cardiovascular events and malignancy. To overcome these limitations, injectable hydrogels are engineered for the local and sustained delivery of baricitinib, a representative JAK inhibitor. Hydrogels are formed via disulfide crosslinking of thiolated hyaluronic acid macromers. Dynamic thioimidate bonds are introduced between the thiolated hyaluronic acid and nitrile-containing baricitinib for drug tethering, which is confirmed with 1H and 13C nuclear magnetic resonance (NMR). Release of baricitinib is tunable over six weeks in vitro and active in inhibiting JAK signaling in a cell line containing a luciferase reporter reflecting interferon signaling. For in vivo activity, baricitinib hydrogels or controls are injected intradermally into an imiquimod-induced mouse model of psoriasis. Imiquimod increases epidermal thickness in mice, which is unaffected when treated with baricitinib or hydrogel alone. Treatment with baricitinib hydrogels suppresses the increased epidermal thickness in mice treated with imiquimod, suggesting that the sustained and local release of baricitinib is important for a therapeutic outcome. This study is the first to utilize a thioimidate chemistry to deliver JAK inhibitors to the skin through injectable hydrogels, which has translational potential for treating inflammatory disorders.

Microinterfaces in biopolymer-based bicontinuous hydrogels guide rapid 3D cell migration.

Cell migration is critical for tissue development and regeneration but requires extracellular environments that are conducive to motion. Cells may actively generate migratory routes in vivo by degrading or remodeling their environments or instead utilize existing extracellular matrix microstructures or microtracks as innate pathways for migration. While hydrogels in general are valuable tools for probing the extracellular regulators of 3-dimensional migration, few recapitulate these natural migration paths. Here, we develop a biopolymer-based bicontinuous hydrogel system that comprises a covalent hydrogel of enzymatically crosslinked gelatin and a physical hydrogel of guest and host moieties bonded to hyaluronic acid. Bicontinuous hydrogels form through controlled solution immiscibility, and their continuous subdomains and high micro-interfacial surface area enable rapid 3D migration, particularly when compared to homogeneous hydrogels. Migratory behavior is mesenchymal in nature and regulated by biochemical and biophysical signals from the hydrogel, which is shown across various cell types and physiologically relevant contexts (e.g., cell spheroids, ex vivo tissues, in vivo tissues). Our findings introduce a design that leverages important local interfaces to guide rapid cell migration.

Identifying constitutive and context-specific molecular-tension-sensitive protein recruitment within focal adhesions.

Mechanosensitive processes often rely on adhesion structures to strengthen, or mature, in response to applied loads. However, a limited understanding of how the molecular tensions that are experienced by a particular protein affect the recruitment of other proteins represents a major obstacle in the way of deciphering molecular mechanisms that underlie mechanosensitive processes. Here, we describe an imaging-based technique, termed fluorescence-tension co-localization (FTC), for studying molecular-tension-sensitive protein recruitment inside cells. Guided by discrete time Markov chain simulations of protein recruitment, we integrate immunofluorescence labeling, molecular tension sensors, and machine learning to determine the sensitivity, specificity, and context dependence of molecular-tension-sensitive protein recruitment. The application of FTC to the mechanical linker protein vinculin in mouse embryonic fibroblasts reveals constitutive and context-specific molecular-tension-sensitive protein recruitment that varies with adhesion maturation. FTC overcomes limitations associated with the alteration of numerous proteins during the manipulation of cell contractility, providing molecularly specific insights into tension-sensitive protein recruitment.

A Fully Automated Post-Surgical Brain Tumor Segmentation Model for Radiation Treatment Planning and Longitudinal Tracking.

Glioblastoma (GBM) has a poor survival rate even with aggressive surgery, concomitant radiation therapy (RT), and adjuvant chemotherapy. Standard-of-care RT involves irradiating a lower dose to the hyperintense lesion in T2-weighted fluid-attenuated inversion recovery MRI (T2w/FLAIR) and a higher dose to the enhancing tumor on contrast-enhanced, T1-weighted MRI (CE-T1w). While there have been several attempts to segment pre-surgical brain tumors, there have been minimal efforts to segment post-surgical tumors, which are complicated by a resection cavity and postoperative blood products, and tools are needed to assist physicians in generating treatment contours and assessing treated patients on follow up. This report is one of the first to train and test multiple deep learning models for the purpose of post-surgical brain tumor segmentation for RT planning and longitudinal tracking. Post-surgical FLAIR and CE-T1w MRIs, as well as their corresponding RT targets (GTV1 and GTV2, respectively) from 225 GBM patients treated with standard RT were trained on multiple deep learning models including: Unet, ResUnet, Swin-Unet, 3D Unet, and Swin-UNETR. These models were tested on an independent dataset of 30 GBM patients with the Dice metric used to evaluate segmentation accuracy. Finally, the best-performing segmentation model was integrated into our longitudinal tracking web application to assign automated structured reporting scores using change in percent cutoffs of lesion volume. The 3D Unet was our best-performing model with mean Dice scores of 0.72 for GTV1 and 0.73 for GTV2 with a standard deviation of 0.17 for both in the test dataset. We have successfully developed a lightweight post-surgical segmentation model for RT planning and longitudinal tracking.

Microinterfaces in bicontinuous hydrogels guide rapid 3D cell migration.

Cell migration is critical for tissue development and regeneration but requires extracellular environments that are conducive to motion. Cells may actively generate migratory routes in vivo by degrading or remodeling their environments or may instead utilize existing ECM microstructures or microtracks as innate pathways for migration. While hydrogels in general are valuable tools for probing the extracellular regulators of 3D migration, few have recapitulated these natural migration paths. Here, we developed a biopolymer-based (i.e., gelatin and hyaluronic acid) bicontinuous hydrogel system formed through controlled solution immiscibility whose continuous subdomains and high micro-interfacial surface area enabled rapid 3D migration, particularly when compared to homogeneous hydrogels. Migratory behavior was mesenchymal in nature and regulated by biochemical and biophysical signals from the hydrogel, which was shown across various cell types and physiologically relevant contexts (e.g., cell spheroids, ex vivo tissues, in vivo tissues). Our findings introduce a new design that leverages important local interfaces to guide rapid cell migration.

All in the Family: A Qualitative Study of the Early Experiences of Adults with Younger Onset Type 2 Diabetes.

OBJECTIVE: Adults with type 2 diabetes diagnosed at a younger age are at increased risk for poor outcomes. We examined life stage-related facilitators and barriers to early self-management among younger adults with newly diagnosed type 2 diabetes. RESEARCH DESIGN AND METHODS: We conducted 6 focus groups that each met twice between November 2017 and May 2018. Participants (n = 41) were aged 21 to 44 years and diagnosed with type 2 diabetes during the prior 2 years. Transcripts were coded using thematic analysis and themes were mapped to the Capability-Opportunity-Motivation-Behavior framework. RESULTS: Participants were 38.4 (±5.8) years old; 10 self-identified as Latinx, 12 as Black, 12 as White, and 7 as multiple or other races. We identified 9 themes that fell into 2 categories: (1) the impact of having an adult family member with diabetes, and (2) the role of nonadult children. Family members with diabetes served as both positive and negative role models, and, for some, personal familiarity with the disease made adjusting to the diagnosis easier. Children facilitated their parents' self-management by supporting self-management activities and motivating their parents to remain healthy. However, the stress and time demands resulting from parental responsibilities and the tendency to prioritize children's needs were perceived as barriers to self-management. CONCLUSIONS: Our results highlight how the life position of younger-onset individuals with type 2 diabetes influences their early experiences. Proactively addressing perceived barriers to and facilitators of self-management in the context of family history and parenthood may aid in efforts to support these high-risk, younger patients.

Final Report on Clinical Outcomes and Tumor Recurrence Patterns of a Pilot Study Assessing Efficacy of Belinostat (PXD-101) with Chemoradiation for Newly Diagnosed Glioblastoma.

Glioblastoma (GBM) is highly aggressive and has a poor prognosis. Belinostat is a histone deacetylase inhibitor with blood-brain barrier permeability, anti-GBM activity, and the potential to enhance chemoradiation. The purpose of this clinical trial was to assess the efficacy of combining belinostat with standard-of-care therapy. Thirteen patients were enrolled in each of control and belinostat cohorts. The belinostat cohort was given a belinostat regimen (500-750 mg/m2 1×/day × 5 days) every three weeks (weeks 0, 3, and 6 of RT). All patients received temozolomide and radiation therapy (RT). RT margins of 5-10 mm were added to generate clinical tumor volumes and 3 mm added to create planning target volumes. Median overall survival (OS) was 15.8 months for the control cohort and 18.5 months for the belinostat cohort (p = 0.53). The recurrence volumes (rGTVs) for the control cohort occurred in areas that received higher radiation doses than that in the belinostat cohort. For those belinostat patients who experienced out-of-field recurrence, tumors were detectable by spectroscopic MRI before RT. Recurrence analysis suggests better in-field control with belinostat. This study highlights the potential of belinostat as a synergistic therapeutic agent for GBM. It may be particularly beneficial to combine this radio-sensitizing effect with spectroscopic MRI-guided RT.

Effects of Parasitoid Age, Host Egg Age, and Host Egg Freezing on Reproductive Success of Ooencyrtus mirus (Hymenoptera: Encyrtidae) on Bagrada hilaris (Hemiptera: Pentatomidae) Eggs.

Bagrada hilaris (Burmeister) is a serious pest on brassica crops in many regions throughout the world. As part of our efforts to enhance biological control, we have been studying an egg parasitoid that was collected from B. hilaris eggs found on brassica plant debris in Pakistan. This species has recently been described as Ooencyrtus mirus Triapitsyn & Power. A major component of rearing biological control agents is understanding the relationship among host egg age, parasitoid age, and reproductive success. To this end, we used a factorial design to evaluate all combinations of host egg ages 0-5 d and parasitoid ages 0-11 d. The results showed that the best combinations are 0- to 1-d-old host eggs with 3- to 10-d-old parasitoids. A further study using frozen host eggs showed that O. mirus can reproduce as successfully on frozen B. hilaris eggs as on fresh ones.

Dimensions of Service Quality in Health-Fitness Clubs in China.

The purpose of this study was to explore the dimensions of service quality in fitness clubs in China and examine their impact on customer satisfaction. In Phase I of the study, we collected qualitative data from online comments related to service quality in 30 Tera Wellness clubs in Shanghai (k = 6252). Conducting content analysis, we synthesized the information and identified preliminary themes and formulated measurement statements. Phase II implemented a series of quantitative research procedures to examine the measurement properties of statements developed in Phase I. Conducting exploratory factor analysis, confirmatory factor analysis, and structural equation modeling analyses based on responses of club members (N = 533), we identified a total of 27 items in six dimensions: service recovery, service assurance, facility function, program operation, instructor quality, and staff performance. These factors significantly (p < 0.05) predicted customer satisfaction with fitness clubs in China. The findings highlight the importance of high-quality service delivery, service recovery, and service assurance and pinpoint specific areas for improvement.

Changing Incidence and Mechanism of Pregnancy-Associated Myocardial Infarction in the State of California.

Background The objective of this study was to evaluate the temporal trends in pregnancy-associated myocardial infarction (PAMI) in the State of California and explore potential risk factors and mechanisms. Methods and Results The California State Inpatient Database was analyzed from 2003 to 2011 for patients with International Classification of Diseases, Ninth Revision (ICD-9) codes for acute myocardial infarction and pregnancy or postpartum admissions; risk factors were analyzed and compared with pregnant patients without myocardial infarction. A total of 341 patients were identified with PAMI from a total of 5 266 380 pregnancies (incidence of 6.5 per 100 000 pregnancies). Inpatient maternal mortality rate was 7%, and infant mortality rate was 3.5% among patients with PAMI. There was a nonsignificant trend toward an increase in PAMI incidence from 2003 to 2011, possibly attributable to higher incidence of spontaneous coronary artery dissection, vasospasm, and Takotsubo syndrome. PAMI, when compared with pregnant patients without myocardial infarction, was significant for older age (aged >30 years in 72% versus 37%, P<0.0005), higher preponderance of Black race (12% versus 6%, P<0.00005), lower socioeconomic status (median household income in lowest quartile 26% versus 20%, P=0.04), higher prevalence of hypertension (26% versus 7%, P<0.0005), diabetes (7% versus 1%, P<0.0005), anemia (31% versus 7%, P<0.0001), amphetamine use (1% versus 0%, P<0.00005), cocaine use (2% versus 0.2%, P<0.0001), and smoking (6% versus 1%, P=0.0001). Conclusions There has been a trend toward an increase in PAMI incidence in California over the past decade, with an increasing trend in spontaneous coronary artery dissection, vasospasm, and Takotsubo syndrome as mechanisms. These findings warrant further investigation.

Programmable and contractile materials through cell encapsulation in fibrous hydrogel assemblies.

The natural extracellular matrix (ECM) within tissues is physically contracted and remodeled by cells, allowing the collective shaping of functional tissue architectures. Synthetic materials that facilitate self-assembly similar to natural ECM are needed for cell culture, tissue engineering, and in vitro models of development and disease. To address this need, we develop fibrous hydrogel assemblies that are stabilized with photocrosslinking and display fiber density­dependent strain-responsive properties (strain stiffening and alignment). Encapsulated mesenchymal stromal cells locally contract low fiber density assemblies, resulting in macroscopic volumetric changes with increased cell densities and moduli. Because of properties such as shear-thinning and self-healing, assemblies can be processed into microtissues with aligned ECM deposition or through extrusion bioprinting and photopatterning to fabricate constructs with programmed shape changes due to cell contraction. These materials provide a synthetic approach to mimic features of natural ECM, which can now be processed for applications in biofabrication and tissue engineering.