The Sister Study was designed to address gaps in the study of environment and breast cancer by taking advantage of more frequent breast cancer diagnoses among women with a sister history of breast ...cancer and the presumed enrichment of shared environmental and genetic exposures.
The Sister Study sought a large cohort of women never diagnosed with breast cancer but who had a sister (full or half) diagnosed with breast cancer.
A multifaceted national effort employed novel strategies to recruit a diverse cohort, and collected biological and environmental samples and extensive data on potential breast cancer risk factors.
The Sister Study enrolled 50,884 U.S. and Puerto Rican women 35-74y of age (median 56 y). Although the majority were non-Hispanic white, well educated, and economically well off, substantial numbers of harder-to-recruit women also enrolled (race/ethnicity other than non-Hispanic white: 16%; no college degree: 35%; household income <$50,000: 26%). Although all had a biologic sister with breast cancer, 16.5% had average or lower risk of breast cancer according to the Breast Cancer Risk Assessment Tool (Gail score). Most were postmenopausal (66%), parous with a first full-term pregnancy <30y of age (79%), never-smokers (56%) with body mass indexes (BMIs) of <29.9
kg/m
(70%). Few (5%) reported any cancer prior to enrollment.
The Sister Study is a unique cohort designed to efficiently study environmental and genetic risk factors for breast cancer. Extensive exposure data over the life-course and baseline specimens provide important opportunities for studying breast cancer and other health outcomes in women. Collaborations are welcome. https://doi.org/10.1289/EHP1923.
The Routledge Companion to African American Theatre and Performance is an outstanding collection of specially written essays that charts the emergence, development, and diversity of African American ...Theatre and Performance—from the nineteenth-century African Grove Theatre to Afrofuturism. Alongside chapters from scholars are contributions from theatre makers, including producers, theatre managers, choreographers, directors, designers, and critics. This ambitious Companion includes:A "Timeline of African American theatre and performance."Part I "Seeing ourselves onstage" explores the important experience of Black theatrical self-representation. Analyses of diverse topics including historical dramas, Broadway musicals, and experimental theatre allow readers to discover expansive articulations of Blackness.Part II "Institution building" highlights institutions that have nurtured Black people both on stage and behind the scenes. Topics include Historically Black Colleges and Universities (HBCUs), festivals, and black actor training.Part III "Theatre and social change" surveys key moments when Black people harnessed the power of theatre to affirm community realities and posit new representations for themselves and the nation as a whole. Topics include Du Bois and African Muslims, women of the Black Arts Movement, Afro-Latinx theatre, youth theatre, and operatic sustenance for an Afro future.Part IV "Expanding the traditional stage" examines Black performance traditions that privilege Black worldviews, sense-making, rituals, and innovation in everyday life. This section explores performances that prefer the space of the kitchen, classroom, club, or field.This book engages a wide audience of scholars, students, and theatre practitioners with its unprecedented breadth. More than anything, these invaluable insights not only offer a window onto the processes of producing work, but also the labour and economic issues that have shaped and enabled African American theatre.
Many bacteria contain an ortholog of the Ro autoantigen, a ring-shaped protein that binds noncoding RNAs (ncRNAs) called Y RNAs. In the only studied bacterium, Deinococcus radiodurans, the Ro ...ortholog Rsr functions in heat-stress-induced ribosomal RNA (rRNA) maturation and starvation-induced rRNA decay. However, the mechanism by which this conserved protein and its associated ncRNAs act has been obscure. We report that Rsr and the exoribonuclease polynucleotide phosphorylase (PNPase) form an RNA degradation machine that is scaffolded by Y RNA. Single-particle electron microscopy, followed by docking of atomic models into the reconstruction, suggests that Rsr channels single-stranded RNA into the PNPase cavity. Biochemical assays reveal that Rsr and Y RNA adapt PNPase for effective degradation of structured RNAs. A Ro ortholog and ncRNA also associate with PNPase in Salmonella Typhimurium. Our studies identify another ribonucleoprotein machine and demonstrate that ncRNA, by tethering a protein cofactor, can alter the substrate specificity of an enzyme.
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► A bacterial Ro protein is complexed with ncRNA and the PNPase exoribonuclease ► ncRNA scaffolds this RNA degradation machine ► Single-particle EM suggests that Rsr channels RNA into the PNPase cavity ► Rsr and the ncRNA specialize PNPase for degrading structured RNA
A bacterial Y noncoding RNA is found to tether Ro protein to polynucleotide phosphorylase exoribonuclease, specializing this enzyme for degrading structured RNAs. Thus, a noncoding RNA can alter the substrate specificity of an enzyme by tethering a protein cofactor.
Background
Sliding hiatal herniation (SHH) and gastroesophageal reflux (GER) commonly occur in French bulldogs. Wireless pH monitoring can quantitatively assess acidic GER in dogs affected by SHH.
...Hypothesis/Objectives
Measure acidic GER in French bulldogs with SHH, pre‐ and post‐brachycephalic obstructive airway syndrome (BOAS) surgery, utilizing a wireless pH capsule (Bravo Calibration‐free, Medtronic, Minnesota), and correlate with owners' observations of regurgitation.
Animals
Eleven French bulldogs diagnosed with SHH via swallowing fluoroscopy.
Methods
Prospective cohort study. A pH capsule was endoscopically placed in the esophagus. Up to 96 hours of data were acquired as the owner logged clinical signs. Spearman's correlation and Wilcoxon rank‐sum tests evaluated factors correlated with acid exposure time (AET), defined by the % time pH < 4. In 4/11 dogs, Bravo monitoring was repeated 2‐4 months after BOAS surgery.
Results
Medians (Q1‐Q3) for age and weight were 21 months (17‐35.5) and 10.0 kg (8.9‐11.5). BOAS severity was mild (3), moderate (4), or severe (4). Medians (Q1‐Q3) for AET and reflux events were 3.3% (2.6‐6.4) and 70 (34‐173). Clinical score (P = .82) and BOAS severity (P = .60) were not correlated with AET, but age was negatively correlated (rho = −.66, P = .03). Median probability (Q1‐Q3) that regurgitation was associated with a reflux event was 72.5% (0‐99). Percent AET numerically improved in all 4 dogs that underwent BOAS surgery although not statistically assessed.
Conclusions and Clinical Importance
Wireless pH monitoring documented acidic GER in French bulldogs with SHH, captured subclinical events, and showed improvements after BOAS surgery.
Modifiable risk factors such as smoking and sedentary lifestyle adversely affect multiple sclerosis (MS) progression. Few multimodal behavioural interventions have been conducted for people with MS, ...and follow-up beyond 1 year is rare for lifestyle interventions. This study assessed adoption and adherence to healthy lifestyle behaviours and health outcomes 3 years after a lifestyle modification intervention, using generalized estimating equation models to account for within-participant correlation over time.
95 people with MS completed baseline surveys before participating in 5-day MS lifestyle risk-factor modification workshops. 76 and 78 participants completed the 1-year and 3-year follow-up surveys respectively. Mean age at 3-year follow-up was 47 years, 72% were female, most (62.8%) had MS for 5 years or less, and 73% had relapsing remitting MS (RRMS).
Compared to baseline, participants reported clinically meaningful increases in physical (mean difference (MD): 8.0, 95% Confidence Interval (CI): 5.2-10.8) and mental health (MD: 9.2, CI: 5.8-12.6) quality of life (QOL) at 1-year, and physical (MD: 8.7, CI: 5.3-12.2) and mental health (MD: 8.0, CI: 4.2-11.8) QOL at 3-year follow-up. There was a small decrease in disability from baseline to 1-year follow-up (MD: 0.9, CI: 0.9,1.0) and to 3-year follow-up (MD: 1.0, CI: 0.9,1.0), which was not clinically meaningful. Of those with RRMS, compared to baseline, fewer had a relapse during the year before 1-year follow-up (OR: 0.1, CI 0.0-0.2) and 3-year follow-up (OR: 0.15, CI 0.06-0.33). Participants' healthy diet score, the proportion meditating ≥1 hours a week, supplementing with ≥ 5000IU vitamin D daily, and supplementing with omega-3 flaxseed oil increased at 1-year follow-up and was sustained, although slightly lower at 3-year follow-up. However, there was no evidence for a change in physical activity and not enough smokers to make meaningful comparisons. Medication use increased at 1-year follow-up and at 3-year follow-up.
The results provide evidence that lifestyle risk factor modification is feasible and sustainable over time, in a small self-selected and motivated sample of people with MS. Furthermore, participation in a lifestyle intervention is not associated with a decrease in MS medication use.
Previous studies indicated that glycans in serum may serve as biomarkers for diagnosis of ovarian cancer; however, it was unclear to which proteins these glycans belong. We hypothesize that ...protein-specific glycosylation profiles of the glycans may be more informative of ovarian cancer and can provide insight into biological mechanisms underlying glycan aberration in serum of diseased individuals. Serum samples from women diagnosed with epithelial ovarian cancer (EOC, n = 84) and matched healthy controls (n = 84) were obtained from the Gynecologic Oncology Group. Immunoglobulin (IgG, IgA, and IgM) concentrations and glycosylation profiles were quantified using multiple reaction monitoring mass spectrometry. Differential and classification analyses were performed to identify aberrant protein-specific glycopeptides using a training set. All findings were validated in an independent test set. Multiple glycopeptides from immunoglubins IgA, IgG, and IgM were found to be differentially expressed in serum of EOC patients compared with controls. The protein-specific glycosylation profiles showed their potential in the diagnosis of EOC. In particular, IgG-specific glycosylation profiles are the most powerful in discriminating between EOC case and controls. Additional studies of protein- and site-specific glycosylation profiles of immunoglobulins and other proteins will allow further elaboration on the characteristics of biological functionality and causality of the differential glycosylation in ovarian cancer and thus ultimately lead to increased sensitivity and specificity of diagnosis.
Kidney cancer often diagnosed at late stages when treatment options are severely limited. Thus, greater understanding of tumor metabolism leading ultimately to novel approaches to diagnosis is ...needed. Our laboratory has been utilizing metabolomics to evaluate compounds appearing in kidney cancer patients' biofluids at concentrations different from control patients. Here, we collected urine samples from kidney cancer patients and analyzed them by chromatography coupled to mass spectrometry. Once normalized to control for urinary concentration, samples were analyzed by two independent laboratories. After technical validation, we now show differential urinary concentrations of several acylcarnitines as a function of both cancer status and kidney cancer grade, with most acylcarnitines being increased in the urine of cancer patients and in those patients with high cancer grades. This finding was validated in a mouse xenograft model of human kidney cancer. Biological validation shows carbon chain length‐dependent effects of the acylcarnitines on cytotoxicity in vitro, and higher chain length acylcarnitines demonstrated inhibitory effects on NF‐κB activation, suggesting an immune modulatory effect of these compounds. Thus, acylcarnitines in the kidney cancer urine may reflect alterations in metabolism, cell component synthesis and/or immune surveillance, and may help explain the profound chemotherapy resistance seen with this cancer. This study shows for the first time the value of a novel class of metabolites which may lead to new therapeutic approaches for cancer and may prove useful in cancer biomarker studies. Furthermore, these findings open up a new area of investigation into the metabolic basis of kidney cancer.
Findings regarding phenotypic differences between boys and girls with ASD are mixed. We compared autism and internalizing symptoms in a sample of 8-18 year-old girls (
n
= 20) and boys (
n
= 20) ...with ASD and typically developing (TYP) girls (
n
= 19) and boys (
n
= 17). Girls with ASD were more impaired than TYP girls but did not differ from boys with ASD in autism symptoms. In adolescence, girls with ASD had higher internalizing symptoms than boys with ASD and TYP girls, and higher symptoms of depression than TYP girls. Girls ages 8-18 with ASD resemble boys with ASD and not TYP girls, and appear to be at increased risk for affective symptoms in the teen years.
While metabolomics has tremendous potential for diagnostic biomarker and therapeutic target discovery, its utility may be diminished by the variability that occurs due to environmental exposures ...including diet and the influences of the human circadian rhythm. For successful translation of metabolomics findings into the clinical setting, it is necessary to exhaustively define the sources of metabolome variation. To address these issues and to measure the variability of urinary and plasma metabolomes throughout the day, we have undertaken a comprehensive inpatient study in which we have performed non-targeted metabolomics analysis of blood and urine in 26 volunteers (13 healthy subjects with no known disease and 13 healthy subjects with autosomal dominant polycystic kidney disease not taking medication). These individuals were evaluated in a clinical research facility on two separate occasions, over three days, while on a standardized, weight-based diet. Subjects provided pre- and post-prandial blood and urine samples at the same time of day, and all samples were analyzed by "fast lane" LC-MS-based global metabolomics. The largest source of variability in blood and urine metabolomes was attributable to technical issues such as sample preparation and analysis, and less variability was due to biological variables, meals, and time of day. Higher metabolome variability was observed after the morning as compared to the evening meal, yet day-to-day variability was minimal and urine metabolome variability was greater than that of blood. Thus we suggest that blood and urine are suitable biofluids for metabolomics studies, though nontargeted mass spectrometry alone may not offer sufficient precision to reveal subtle changes in the metabolome. Additional targeted analyses may be needed to support the data from nontargeted mass spectrometric analyses. In light of these findings, future metabolomics studies should consider these sources of variability to allow for appropriate metabolomics testing and reliable clinical translation of metabolomics data.
For most classes of drugs, rapid development of therapeutics to treat emerging infections is challenged by the timelines needed to identify compounds with the desired efficacy, safety, and ...pharmacokinetic profiles. Fully human monoclonal antibodies (mAbs) provide an attractive method to overcome many of these hurdles to rapidly produce therapeutics for emerging diseases.
In this study, we deployed a platform to generate, test, and develop fully human antibodies to Zaire ebolavirus. We obtained specific anti-Ebola virus (EBOV) antibodies by immunizing VelocImmune mice that use human immunoglobulin variable regions in their humoral responses.
Of the antibody clones isolated, 3 were selected as best at neutralizing EBOV and triggering FcγRIIIa. Binding studies and negative-stain electron microscopy revealed that the 3 selected antibodies bind to non-overlapping epitopes, including a potentially new protective epitope not targeted by other antibody-based treatments. When combined, a single dose of a cocktail of the 3 antibodies protected nonhuman primates (NHPs) from EBOV disease even after disease symptoms were apparent.
This antibody cocktail provides complementary mechanisms of actions, incorporates novel specificities, and demonstrates high-level postexposure protection from lethal EBOV disease in NHPs. It is now undergoing testing in normal healthy volunteers in preparation for potential use in future Ebola epidemics.
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