Uncovering the biology of multiple myeloma among African Americans: a comprehensive genomics approach.

Epidemiological data have suggested that African American (AA) persons are twice as likely to be diagnosed with multiple myeloma (MM) compared with European American (EA) persons. Here, we have analyzed a set of cytogenetic and genomic data derived from AA and EA MM patients. We have compared the frequency of IgH translocations in a series of data from 115 AA patients from 3 studies and 353 EA patients from the Eastern Cooperative Oncology Group (ECOG) studies E4A03 and E9487. We have also interrogated tumors from 45 AA and 196 EA MM patients for somatic copy number abnormalities associated with poor outcome. In addition, 35 AA and 178 EA patients were investigated for a transcriptional profile associated with high-risk disease. Overall, based on this cohort, genetic profiles were similar except for a significantly lower frequency of IgH translocations (40% vs 52%; P = .032) in AA patients. Frequency differences of somatic copy number aberrations were not significant after correction for multiple testing. There was also no significant difference in the frequency of high-risk disease based on gene expression profiling. Our study represents the first comprehensive comparisons of the frequency and distribution of molecular alterations in MM tumors between AA and EA patients. ECOG E4A03 is registered with ClinicalTrials.gov, number NCT00098475. ECOG E9487 is a companion validation set to the ECOG study E9486 and is registered with the National Institutes of Health, National Cancer Institute, Clinical Trials (PDQ), number EST-9486.

Boric acid induces cytoplasmic stress granule formation, eIF2α phosphorylation, and ATF4 in prostate DU-145 cells.

Dietary boron intake is associated with reduced prostate and lung cancer risk and increased bone mass. Boron is absorbed and circulated as boric acid (BA) and at physiological concentrations is a reversible competitive inhibitor of cyclic ADP ribose, the endogenous agonist of the ryanodine receptor calcium (Ca(+2)) channel, and lowers endoplasmic reticulum (ER) [Ca(2+)]. Low ER [Ca(2+)] has been reported to induce ER stress and activate the eIF2α/ATF4 pathway. Here we report that treatment of DU-145 prostate cells with physiological levels of BA induces ER stress with the formation of stress granules and mild activation of eIF2α, GRP78/BiP, and ATF4. Mild activation of eIF2α and its downstream transcription factor, ATF4, enables cells to reconfigure gene expression to manage stress conditions and mild activation of ATF4 is also required for the differentiation of osteoblast cells. Our results using physiological levels of boric acid identify the eIF2α/ATF pathway as a plausible mode of action that underpins the reported health effects of dietary boron.

Psychosocial distress and stroke risk in older adults.

BACKGROUND AND PURPOSE: To investigate the association of psychosocial distress with risk of stroke mortality and incident stroke in older adults. METHODS: Data were from the Chicago Health and Aging Project, a longitudinal population-based study conducted in 3 contiguous neighborhoods on the south side of Chicago, IL. Participants were community-dwelling black and non-Hispanic white adults, aged 65 years and older (n=4120 for stroke mortality; n=2649 for incident stroke). Psychosocial distress was an analytically derived composite measure of depressive symptoms, perceived stress, neuroticism, and life dissatisfaction. Cox proportional hazards models examined the association of distress with stroke mortality and incident stroke over 6 years of follow-up. RESULTS: Stroke deaths (151) and 452 incident strokes were identified. Adjusting for age, race, and sex, the hazard ratio (HR) for each 1-SD increase in distress was 1.47 (95% confidence interval [CI]=1.28-1.70) for stroke mortality and 1.18 (95% CI=1.07-1.30) for incident stroke. Associations were reduced after adjustment for stroke risk factors and remained significant for stroke mortality (HR=1.29; 95% CI=1.10-1.52) but not for incident stroke (HR=1.09; 95% CI=0.98-1.21). Secondary analyses of stroke subtypes showed that distress was strongly related to incident hemorrhagic strokes (HR=1.70; 95% CI=1.28-2.25) but not ischemic strokes (HR=1.02; 95% CI=0.91-1.15) in fully adjusted models. CONCLUSIONS: Increasing levels of psychosocial distress are related to excess risk of both fatal and nonfatal stroke in older black and white adults. Additional research is needed to examine pathways linking psychosocial distress to cerebrovascular disease risk.

Impact of gene expression profiling-based risk stratification in patients with myeloma receiving initial therapy with lenalidomide and dexamethasone.

Detection of specific chromosomal abnormalities by FISH and metaphase cytogenetics allows risk stratification in multiple myeloma; however, gene expression profiling (GEP) based signatures may enable more specific risk categorization. We examined the utility of 2 GEP-based risk stratification systems among patients undergoing initial therapy with lenalidomide in the context of a phase 3 trial. Among 45 patients studied at baseline, 7 (16%) and 10 (22%), respectively, were high-risk using the GEP70 and GEP15 signatures. The median overall survival for the GEP70 high-risk group was 19 months versus not reached for the rest (hazard ratio = 14.1). Although the medians were not reached, the GEP15 also predicted a poor outcome among the high-risk patients. The C-statistic for the GEP70, GEP15, and FISH based risk stratification systems was 0.74, 0.7, and 0.7, respectively. Here we demonstrate the prognostic value for GEP risk stratification in a group of patients primarily treated with novel agents. This trial was registered at www.clinicaltrials.gov as #NCT00098475.

Monolayer graphene dispersion and radiative cooling for high power LED.

Molecular fan, a radiative cooling by thin film, has been developed and its application for compact electronic devices has been evaluated. The enhanced surface emissivity and heat dissipation efficiency of the molecular fan coating are shown to correlate with the quantization of lattice modes in active nanomaterials. The highly quantized G and 2D bands in graphene are achieved by our dispersion technique, and then incorporated in an organic-inorganic acrylate emulsion to form a coating assembly on heat sinks (for LED and CPU). This water-based dielectric layer coating has been formulated and applied on metal core printed circuit boards. The heat dissipation efficiency and breakdown voltage are evaluated by a temperature-monitoring system and a high-voltage breakdown tester. The molecular fan coating on heat dissipation units is able to decrease the equilibrium junction temperature by 29.1 ° C, while functioning as a dielectric layer with a high breakdown voltage (>5 kV). The heat dissipation performance of the molecular fan coating applied on LED devices shows that the coated 50 W LED gives an enhanced cooling of 20% at constant light brightness. The schematics of monolayer graphene dispersion, undispersed graphene platelet, and continuous graphene sheet are illustrated and discussed to explain the mechanisms of radiative cooling, radiative/non-radiative, and non-radiative heat re-accumulation.

Placenta membranacea.

Placenta membranacea is a rare placental disorder characterized by the presence of fetal membranes (complete or partially) covered by chorionic villi. A 35-year-old woman, gravida 1, was admitted for preterm labor at 24 weeks and 5 days. She subsequently developed heavy vaginal bleeding and underwent a classical cesarean delivery for suspected abruption. Postpartum inspection of the placenta demonstrated a small placenta with tan colored membranes, and diffusely scattered placental cotyledons. Histologic examination revealed chorionic villi directly attached to the fetal membranes on the periphery,consistent with the diagnosis of a partial placenta membranacea. Placenta membranacea should be considered in the etiology of painless vaginal bleeding in the second and third trimester. This condition can be associated with other placental abnormalities, such as placenta previa or accreta. Perinatal outcome may include stillbirth, preterm delivery, or neonatal death.

Context and Considerations for the Development of Community-Informed Health Communication Messaging to Support Equitable Uptake of COVID-19 Vaccines Among Communities of Color in Washington, DC.

BACKGROUND: Communities of color have been disproportionately impacted by COVID-19. We explored barriers and facilitators to COVID-19 vaccine uptake among African American, Latinx, and African immigrant communities in Washington, DC. METHODS: A total of 76 individuals participated in qualitative interviews and focus groups, and 208 individuals from communities of color participated in an online crowdsourcing contest. RESULTS: Findings documented a lack of sufficient, accurate information about COVID-19 vaccines and questions about the science. African American and African immigrant participants spoke about the deeply rooted historical underpinnings to their community's vaccine hesitancy, citing the prior and ongoing mistreatment of people of color by the medical community. Latinx and African immigrant participants highlighted how limited accessibility played an important role in the slow uptake of COVID-19 vaccines in their communities. Connectedness and solidarity were found to be key assets that can be drawn upon through community-driven responses to address social-structural challenges to COVID-19 related vaccine uptake. CONCLUSIONS: The historic and ongoing socio-economic context and realities of communities of color must be understood and respected to inform community-based health communication messaging to support vaccine equity for COVID-19 and other infectious diseases.

Identification of ryanodine receptor isoforms in prostate DU-145, LNCaP, and PWR-1E cells.

The ryanodine receptor (RyR) is a large, intracellular calcium (Ca(2+)) channel that is associated with several accessory proteins and is an important component of a cell's ability to respond to changes in the environment. Three isoforms of the RyR exist and are well documented for skeletal and cardiac muscle and the brain, but the isoforms in non-excitable cells are poorly understood. The aggressiveness of breast cancers in women has been positively correlated with the expression of the RyR in breast tumor tissue, but it is unknown if this is limited to specific isoforms. Identification and characterization of RyRs in cancer models is important in understanding the role of the RyR channel complex in cancer and as a potential therapeutic target. The objective of this report was to identify the RyR isoforms expressed in widely used prostate cancer cell lines, DU-145 and LNCaP, and the non-tumorigenic prostate cell line, PWR-1E. Oligonucleotide primers specific for each isoform were used in semi-quantitative and real-time PCR to determine the identification and expression levels of the RyR isoforms. RyR1 was expressed in the highest amount in DU-145 tumor cells, expression was 0.48-fold in the non-tumor cell line PWR-1E compared to DU-145 cells, and no expression was observed in LNCaP tumor cells. DU-145 cells had the lowest expression of RyR2. The expression was 26- and 15-fold higher in LNCaP and PWR-1E cells, respectively. RyR3 expression was not observed in any of the cell lines. All cell types released Ca(2+) in response to caffeine showing they had functional RyRs. Total cellular RyR-associated Ca(2+) release is determined by both the number of activated RyRs and its accessory proteins which modulate the receptor. Our results suggest that the correlation between the expression of the RyR and tumor aggression is not related to specific RyR isoforms, but may be related to the activity and number of receptors.

Impact of high-risk classification by FISH: an eastern cooperative oncology group (ECOG) study E4A03.

Lenalidomide with dexamethasone is a standard induction treatment regimen for newly diagnosed myeloma (although a Federal Drug Administration indication is still absent). In the context of the Phase 3 clinical trial E4A03 (lenalidomide plus dexamethasone in low or high doses), we queried whether a fluorescence in situ hybridization (FISH)-based genetic classification into high risk (HR) and standard risk (SR) multiple myeloma (MM) would remain clinically significant. Of 445 E4A03 patients, 126 had FISH analysis; 21 were classified HR with t(4;14), t(14;16), or 17p13 deletions. Median survival follow-up approached 3 years. Patients with FISH data tended to be younger and healthier compared to the rest of the study population and, consequently, had superior overall survival (OS) results. Within the FISH cohort, shorter OS in the HR versus SR group (P = 0·004) corresponded to a hazard ratio of 3·48 [95% confidence interval: (1·42-8·53)], an effect also observed in multivariate analysis. Two-year OS rates were 91% for SR MM and 76% for HR MM. There was also evidence of interaction between risk status and treatment (P = 0·026). HR patients were less likely to attain good partial response (SR 46% and HR 30%, Odds Ratio = 2·0 [0·7-5·6]), but overall response rates were not different. FISH-based risk classification retained prognostic significance in patients receiving lenalidomide-based induction.

Appraisal of immunoglobulin free light chain as a marker of response.

The immunoglobulin free light chain (FLC) assay is an invaluable tool for following patients with oligosecretory plasma cell dyscrasia. Baseline values have also been shown to be prognostic in all plasma cell disorders tested. A looming question, however, is the role it should play in following myeloma patients with disease that is measurable using serum and urine electrophoresis. We used the data and stored samples from a mature Eastern Cooperative Oncology Group clinical trial (E9486) to assess serum levels of FLC at baseline and after 2 months of alkylator-based therapy. For serial determinations, the absolute level of involved serum FLC or the difference of the involved and uninvolved FLC is preferred over the ratio of involved to uninvolved FLC. FLC response after 2 months of therapy was superior to early M-protein measurement to predict overall response. The ideal cut-point for FLC change appears to be between 40% and 50% reduction. The correlation between serial measurements of serum FLC and urine M-protein is inadequate to abolish the serial 24-hour urine protein. Although baseline values of FLC are prognostic in newly diagnosed myeloma patients, serial measurements do not appear to have added value in patients who have M-proteins measurable by electrophoresis.

"Direct to Drug" screening as a precision medicine tool in multiple myeloma.

Seventy-six FDA-approved oncology drugs and emerging therapeutics were evaluated in 25 multiple myeloma (MM) and 15 non-Hodgkin's lymphoma cell lines and in 113 primary MM samples. Ex vivo drug sensitivities were mined for associations with clinical phenotype, cytogenetic, genetic mutation, and transcriptional profiles. In primary MM samples, proteasome inhibitors, dinaciclib, selinexor, venetoclax, auranofin, and histone deacetylating agents had the broadest cytotoxicity. Of interest, newly diagnosed patient samples were globally less sensitive especially to bromodomain inhibitors, inhibitors of receptor tyrosine kinases or non-receptor kinases, and DNA synthesis inhibitors. Clustering demonstrated six broad groupings of drug sensitivity linked with genomic biomarkers and clinical outcomes. For example, our findings mimic clinical observations of increased venetoclax responsiveness in t(11;14) patients but also identify an increased sensitivity profile in untreated patients, standard genetic risk, low plasma cell S-Phase, and in the absence of Gain(1q) and t(4;14). In contrast, increased ex vivo responsiveness to selinexor was associated with biomarkers of poor prognosis and later relapse patients. This "direct to drug" screening resource, paired with functional genomics, has the potential to successfully direct appropriate individualized therapeutic approaches in MM and to enrich clinical trials for likely responders.

Effect of tissue shipping on plasma cell isolation, viability, and RNA integrity in the context of a centralized good laboratory practice-certified tissue banking facility.

The Multiple Myeloma Research Consortium has established a tissue bank for the deposition of bone marrow samples from patients with multiple myeloma to be mailed and processed under good laboratory practices. To date, over 1,000 samples have been collected. At this time, limited information is available on shipped bone marrow aspirates in regards to cell viability, yield, purity, and subsequent RNA yield and quality. To test these determinants, we did a pilot study on behalf of the Multiple Myeloma Research Consortium where samples were drawn at Mayo Clinic Rochester (MCR) pooled and split into two equal aliquots. One-half of each sample was processed following good laboratory practices compliant standard operating procedures, immediately after sample procurement, at MCR. The CD138+ cells were stored at -80 degrees C as a Trizol lysate. The other half of the aspirate was sent overnight to Mayo Clinic Scottsdale where they were processed using identical standard operating procedures. The RNA was extracted and analyzed in a single batch at MCR. At both locations, samples were assayed for the following quality determinants: Viability was assessed using a three-color flow cytometric method (CD45, CD38, and 7-AAD). Cell counts were done to determine plasma cell recovery and post-sort purity determined by means of a slide-based immunofluorescent assay. RNA recovery and integrity was assessed using the Agilent Bioanalyzer. Lastly, gene expression profiles were compared to determine the signature emanating from the shipment of samples. Despite minor differences, our results suggest that shipment of samples did not significantly affect these quality determinants in aggregate.

Every time you go away: changes in affect, behavior, and physiology associated with travel-related separations from romantic partners.

This study investigated changes in day-to-day affect, behavior, and physiology (hypothalamic-pituitary-adrenocortical axis activity) associated with temporary physical separations from romantic partners (such as those brought about by work-related travel). Daily diaries and measures of salivary cortisol were collected from 42 couples over a 21-day period that was timed to coincide with a naturally occurring 4- to 7-day separation. There were significant changes from preseparation to separation and from separation to reunion in the quality of partners' interactions, their positive and negative affect, sleeping problems, subjective stress, physical symptoms, and cortisol levels. Separation and reunion effects were generally more pronounced in homebound partners, partners with high attachment anxiety, and partners who had less contact with each other during the separation. Separation and reunion effects were not moderated by relationship length, relationship satisfaction, how often couples underwent separations, or the presence of children in the home. The results are discussed with respect to the role of daily proximity and contact between partners for day-to-day affective and physiological regulation.

Clinical trials: the art of enrollment.

OBJECTIVES: Enrollment barriers and multidisciplinary approaches to increase cancer trials participation are presented. Recruitment barriers, research in Maryland, and a Best Practice for cancer trials are discussed. DATA SOURCES: Journal and research articles, web sites. CONCLUSION: Clinical trials have produced prevention and care advances for cancer and other diseases. Trial enrollment is lower for minorities and underserved communities. A comprehensive program for addressing enrollment barriers should incorporate research on barriers, multidisciplinary teams, and education and trial infrastructure in community settings. IMPLICATIONS FOR NURSING PRACTICE: Health disparities training, including culturally appropriate enrollment approaches for education and retention of underserved communities, should incorporate community stakeholders and nurse/physician researchers.

Microbiota-driven interleukin-17-producing cells and eosinophils synergize to accelerate multiple myeloma progression.

The gut microbiota has been causally linked to cancer, yet how intestinal microbes influence progression of extramucosal tumors is poorly understood. Here we provide evidence implying that Prevotella heparinolytica promotes the differentiation of Th17 cells colonizing the gut and migrating to the bone marrow (BM) of transgenic Vk*MYC mice, where they favor progression of multiple myeloma (MM). Lack of IL-17 in Vk*MYC mice, or disturbance of their microbiome delayed MM appearance. Similarly, in smoldering MM patients, higher levels of BM IL-17 predicted faster disease progression. IL-17 induced STAT3 phosphorylation in murine plasma cells, and activated eosinophils. Treatment of Vk*MYC mice with antibodies blocking IL-17, IL-17RA, and IL-5 reduced BM accumulation of Th17 cells and eosinophils and delayed disease progression. Thus, in Vk*MYC mice, commensal bacteria appear to unleash a paracrine signaling network between adaptive and innate immunity that accelerates progression to MM, and can be targeted by already available therapies.

Adapting evidence-based strategies to increase physical activity among African Americans, Hispanics, Hmong, and Native Hawaiians: a social marketing approach.

INTRODUCTION: Using a social marketing approach, we studied how best to adapt proven, evidence-based strategies to increase physical activity for use with underserved racial or ethnic groups. METHODS: We conducted focus groups with low-income Hispanic women in Texas, Hmong parents and their children in California, low-income African American women and men in the Mississippi Delta, and Native Hawaiian college students in Hawaii. We also interviewed key leaders of these communities. Topics of discussion were participants' perceptions about 1) the benefits of engaging in physical activity, 2) the proposed evidence-based strategies for increasing each community's level of physical activity, and 3) the benefits and barriers to following the proposed interventions for increasing physical activity. A total of 292 individuals participated in the study. RESULTS: All groups considered that being physically active was part of their culture, and participants found culturally relevant suggestions for physical activities appealing. Overwhelmingly, strategies that aimed to create or improve social support and increase access to physical activity venues received the most positive feedback from all groups. Barriers to physical activity were not culturally specific; they are common to all underserved people (lack of time, transportation, access, neighborhood safety, or economic resources). CONCLUSION: Results indicate that evidence-based strategies to increase physical activity need to be adapted for cultural relevance for each racial or ethnic group. Our research shows that members of four underserved populations are likely to respond to strategies that increase social support for physical activity and improve access to venues where they can be physically active. Further research is needed to test how to implement such strategies in ways that are embraced by community members.

Activation of the EIF2α/ATF4 and ATF6 Pathways in DU-145 Cells by Boric Acid at the Concentration Reported in Men at the US Mean Boron Intake.

Fruits, nuts, legumes, and vegetables are rich sources of boron (B), an essential plant nutrient with chemopreventive properties. Blood boric acid (BA) levels reflect recent B intake, and men at the US mean intake have a reported non-fasting level of 10 µM. Treatment of DU-145 prostate cancer cells with physiological concentrations of BA inhibits cell proliferation without causing apoptosis and activates eukaryotic initiation factor 2 (eIF2α). EIF2α induces cell differentiation and protects cells by redirecting gene expression to manage endoplasmic reticulum stress. Our objective was to determine the temporal expression of endoplasmic reticulum (ER) stress-activated genes in DU-145 prostate cells treated with 10 µM BA. Immunoblots showed post-treatment increases in eIF2α protein at 30 min and ATF4 and ATF6 proteins at 1 h and 30 min, respectively. The increase in ATF4 was accompanied by an increase in the expression of its downstream genes growth arrest and DNA damage-induced protein 34 (GADD34) and homocysteine-induced ER protein (Herp), but a decrease in GADD153/CCAAT/enhancer-binding protein homologous protein (CHOP), a pro-apoptotic gene. The increase in ATF6 was accompanied by an increase in expression of its downstream genes GRP78/BiP, calreticulin, Grp94, and EDEM. BA did not activate IRE1 or induce cleavage of XBP1 mRNA, a target of IRE1. Low boron status has been associated with increased cancer risk, low bone mineralization, and retinal degeneration. ATF4 and BiP/GRP78 function in osteogenesis and bone remodeling, calreticulin is required for tumor suppressor p53 function and mineralization of teeth, and BiP/GRP78 and EDEM prevent the aggregation of misfolded opsins which leads to retinal degeneration. The identification of BA-activated genes that regulate its phenotypic effects provides a molecular underpinning for boron nutrition and biology.

Antibiotic stewardship in the retail clinic setting: Implementation in 1100 clinics nationwide.

In light of increasing antibiotic resistance and a slowed antibiotic development pipeline, stewardship is more urgent than ever. To date, most stewardship guidelines and best practice recommendations for implementation focus on local or regional health care organizations. CVS MinuteClinic has implemented a consistent, evidence-based stewardship approach in its >1100 clinics in 33 states. The approach is associated with higher quality antibiotic use than that in primary care practices and emergency departments. Given MinuteClinic's scale, sharing this approach and lessons learned may assist other organizations in implementing large-scale stewardship programs that foster judicious use of antibiotics for the public's health.

Biological and prognostic significance of interphase fluorescence in situ hybridization detection of chromosome 13 abnormalities (delta13) in multiple myeloma: an eastern cooperative oncology group study.

Chromosome 13 abnormalities (Delta13) have been associated with an unfavorable prognosis in patients with multiple myeloma (MM). The significance of this has been unresolved because of diverse methods of detection and heterogeneous groups of patients. We conducted a study of Delta13 in patients entered into the Eastern Cooperative Oncology Group trial E9486/E9487. Patients with newly diagnosed MM (median follow-up of survivors >100 months) were studied for Delta13, using bone marrow samples obtained at study enrollment. We used interphase fluorescence in situ hybridization with the probes LSI13 (Rb)/D13S319 with simultaneous immunofluorescence detection of bone marrow plasma cells (PCs). We detected Delta13 in 176 of 325 (54%) evaluable patients. Patients with Delta13 were more likely to have a serum monoclonal protein at a concentration < or =1 g/dl (22 versus 13%; P = 0.04), light-chain-only MM (19.3 versus 10.8%; P = 0.04), gamma light chain (42 versus 28%; P = 0.027), stage III (56 versus 42%; P = 0.014), and be female (60 versus 50%; P = 0.087). The PC labeling index and Delta13 correlated (P = 0.03). Patients with Delta13 were less likely to respond to treatment (74 versus 63%; P = 0.041) and had a significantly shorter median overall survival (34.9 versus 51 months; P = 0.021). The association of Delta13 and survival remained an independent prognostic variable in a regression model. Among patients with Delta13, those receiving IFN had a worse overall survival that those not receiving the medication (P = 0.03). The presence of Delta13 is an important and independent adverse prognostic factor in newly diagnosed MM and is associated with specific biological features.