Radiotherapy is effective in the treatment of cancer but also causes damage to non-cancerous tissue. Pelvic radiotherapy may produce chronic and debilitating bowel symptoms, yet the underlying ...pathophysiology is still undefined. Most notably, although pelvic radiotherapy causes an acute intestinal inflammation there is no consensus on whether the late-phase pathophysiology contains an inflammatory component or not. To address this knowledge gap, we examined the potential presence of a chronic inflammation in mucosal biopsies from irradiated pelvic cancer survivors.
We biopsied 24 cancer survivors two to 20 years after pelvic radiotherapy, and four non-irradiated controls. Using tandem mass tag (TMT) mass spectrometry and mRNA sequencing (mRNA-seq), we charted proteomic and transcriptomic profiles of the mucosal tissue previously exposed to a high or a low/no dose of radiation. Changes in the immune cell populations were determined with flow cytometry. The integrity of the protective mucus layers were determined by permeability analysis and 16S rRNA bacterial detection.
942 proteins were differentially expressed in mucosa previously exposed to a high radiation dose compared to a low radiation dose. The data suggested a chronic low-grade inflammation with neutrophil activity, which was confirmed by mRNA-seq and flow cytometry and further supported by findings of a weakened mucus barrier with bacterial infiltration.
Our results challenge the idea that pelvic radiotherapy causes an acute intestinal inflammation that either heals or turns fibrotic without progression to chronic inflammation. This provides a rationale for exploring novel strategies to mitigate chronic bowel symptoms in pelvic cancer survivors.
This study was supported by the King Gustav V Jubilee Clinic Cancer Foundation (CB), The Adlerbertska Research Foundation (CB), The Swedish Cancer Society (GS), The Swedish State under the ALF agreement (GS and CB), Mary von Sydow’s foundation (MA and VP).
Introduction Insomnia-related sleep disruptions such as short and disturbed sleep have been linked to systemic insulin resistance in young adult populations. However, in older adults, a population ...with both higher prevalence of sleep disturbances and increased risk of type 2 diabetes, whether insomnia symptoms are associated with impaired insulin sensitivity is not clear. We therefore sought to investigate this link in a Swedish population of elderly men. Methods Cross-sectional data from 980 men who participated in the age 70-year investigation of the Uppsala Longitudinal Study of Adult Men was utilized. Self-reported insomnia symptoms including difficulty initiating sleep, early morning awakenings, and frequent use of hypnotics (>3 times/wk) were acquired by questionnaire. Participants underwent the gold-standard hyperinsulinemic-euglycemic clamp technique to assess the insulin sensitivity index (M/I). Differences in M/I between men with and those without insomnia symptoms were determined by analysis of covariance, adjusted for age, body mass index, waist circumference, blood pressure, diabetes, smoking, alcohol intake, and level of leisure time physical activity. Results Our analysis yielded no difference in M/I between men with and without insomnia symptoms (mean difference: -0.20 100 × mg/kgbw/min/mU/L; 95%CI: -0.92, 0.53; P=0.59). Results in non-diabetic and diabetic sub-samples were consistent with the negative finding in total cohort (mean difference: -0.01 100 × mg/kgbw/min/mU/L; 95%CI: -0.84, 0.81; P=0.97 and mean difference: -0.31 100 × mg/kgbw/min/mU/L; 95%CI: -1.25, 0.62; P=0.51, respectively). Conclusion These results suggest that insomnia symptoms may not have an impact on measures of insulin sensitivity in elderly men. Given the mono-gender observational design of our study, future investigations are needed to determine whether experimental sleep manipulations influence systemic insulin sensitivity in both elderly men and women, as has previously been shown in young adult populations. Support (If Any) This work was funded by Åke Wiberg Foundation (M17-0088, M18-0169) (XT), Fredrik and Ingrid Thuring Foundation (2017-00313) (XT), Novo Nordisk Foundation (NNF14OC0009349) (CB), Swedish Brain Research Foundation (CB), and Swedish Research Council (2015-03100) (CB).
•Canonical babbling was observed in English- and Chinese-learning infants with all-day recordings, during social and non-social circumstances.•Amount of canonical babbling was influenced by a ...significant interaction of infant age, language/culture, and social circumstance.•Babbling development involves mutual influences of the social environment on infant behavior and of infant behavior on the social environment.
Canonical babbling (CB) is critical in forming foundations for speech. Research has shown that the emergence of CB precedes first words, predicts language outcomes, and is delayed in infants with several communicative disorders. We seek a naturalistic portrayal of CB development, using all-day home recordings to evaluate the influences of age, language, and social circumstances on infant CB production. Thus we address the nature of very early language foundations and how they can be modulated. This is the first study to evaluate possible interactions of language and social circumstance in the development of babbling. We examined the effects of age (6 and 11 months), language/culture (English and Chinese), and social circumstances (during infant-directed speech IDS, during infant overhearing of adult-directed speech ADS, or when infants were alone) on canonical babbling ratios (CBR = canonical syllables/total syllables). The results showed a three-way interaction of infant age by infant language/culture by social circumstance. The complexity of the results forces us to recognize that a variety of factors can interact in the development of foundations for language, and that both the infant vocal response to the language/culture environment and the language/culture environment of the infant may change across age.
Background: Radiotherapy is effective in the treatment of cancer but also causes damage to non-cancerous tissue. Pelvic radiotherapy may produce chronic and debilitating bowel symptoms, yet the ...underlying pathophysiology is still undefined. Most notably, although pelvic radiotherapy causes an acute intestinal inflammation there is no consensus on whether the late-phase pathophysiology contains an inflammatory component or not. To address this knowledge gap, we examined the potential presence of a chronic inflammation in mucosal biopsies from irradiated pelvic cancer survivors. Methods: We biopsied 24 cancer survivors two to 20 years after pelvic radiotherapy, and four non-irradiated controls. Using tandem mass tag (TMT) mass spectrometry and mRNA sequencing (mRNA-seq), we charted proteomic and transcriptomic profiles of the mucosal tissue previously exposed to a high or a low/no dose of radiation. Changes in the immune cell populations were determined with flow cytometry. The integrity of the protective mucus layers were determined by permeability analysis and 16S rRNA bacterial detection. Findings: 942 proteins were differentially expressed in mucosa previously exposed to a high radiation dose compared to a low radiation dose. The data suggested a chronic low-grade inflammation with neutrophil activity, which was confirmed by mRNA-seq and flow cytometry and further supported by findings of a weakened mucus barrier with bacterial infiltration. Interpretation: Our results challenge the idea that pelvic radiotherapy causes an acute intestinal inflammation that either heals or turns fibrotic without progression to chronic inflammation. This provides a rationale for exploring novel strategies to mitigate chronic bowel symptoms in pelvic cancer survivors. Funding: This study was supported by the King Gustav V Jubilee Clinic Cancer Foundation (CB), The Adlerbertska Research Foundation (CB), The Swedish Cancer Society (GS), The Swedish State under the ALF agreement (GS and CB), Mary von Sydow’s foundation (MA and VP).
Abstract Background We hypothesise that the clinical differences between adult and childhood acute lymphoblastic leukaemia (cALL) arise partly through their origin in developmentally distinct target ...cells. Since cALL frequently initiates in utero we aimed to characterise the earliest stages of lymphoid development in human fetal liver. In parallel we used human pluripotent stem cells (hPSC) to recapitulate fetal liver lymphopoiesis and model the impact of the fusion oncogene ETV6-RUNX1 , the commonest genetic aberration in cALL. Methods H1 human embyronic stem cells and MIFF3 human induced hPSCs (provided by University of Sheffield Centre for Stem Cell Biology) were maintained in vitro with mTeSR1/Matrigel. Vectors were produced by recombineering an ETV6 bacterial artificial chromosome with a custom DNA cassette (GeneArt, ThermoFisher, Waltham MA, USA). Vectors were transfected (Nucleofector II, Lonza, Basle, Switzerland) and G418-selected clones were screened by Southern blot. hPSCs were differentiated by sequential OP9/MS5 coculture. Populations sorted by fluorescence-activated cell sorting were analysed by single cell real-time PCR (Biomark 48.48, Fluidigm, San Fransisco, CA, USA) and 200 cell RNA sequencing. Human fetal livers were donated under informed consent with approval of Lund University Ethical Review Board and the Swedish National Board of Health and Welfare. Findings B lymphopoiesis in the fetal liver was distinct from that in adult bone marrow or neonatal cord blood: the earliest fetal liver B cells did not fully express mature lymphoid effectors and the earliest identified lymphoid-capable progenitors coexpressed both lymphoid and myeloid gene expression programmes. Global and single cell gene expression profiling of B lymphopoietic progenitors generated by in vitro differentiation of hPSCs showed that they share the same transcriptional programme. hPSCs that were CRISPR-engineered to express ETV6-RUNX1 were partly arrested in B cell differentiation at the level of the lymphomyeloid progenitor. B cells that passed this block shared the global gene expression signature of the fetal lymphomyeloid progenitor, and single cell real-time PCR showed that they aberrantly coexpressed B and myeloid lineage genes. Interpretation Our results identify a B lymphoid progenitor in human fetal liver characterised by coexpression of lymphoid and myeloid gene expression programmes and suggest that this progenitor's B myeloid signature provides a permissive transcriptional context for ETV6-RUNX1 to effect a partial differentiation arrest. The developmental specificity of the gene expression signature of this cell could offer unique therapeutic targets, and the hSPC model might provide a novel drug-screening platform. Funding Wellcome Trust Research Training Fellowship and NIHR Academic Clinical Fellowship (SR); Swedish Childhood Cancer Foundation (CB); Bloodwise, Cancer Research UK, Children with Cancer, and Great Ormond Street Hospital Children's Charity (TE).
Cannabis is the most frequently used illicit drug worldwide. Although multiple structural MRI studies of individuals with cannabis use (CB) have been undertaken, the reports of the volume alterations ...in the amygdala, hippocampus, and pallidum are not consistent. This study aims to detect subregion-level morphological alterations, analyze the correlation areas with cannabis usage characteristics, and gain new insights into the neuro mechanisms of CB.
By leveraging the novel surface-based subcortical morphometry method, 20 CB and 22 age- and sex-matched healthy controls (HC) were included to explore their volumetric and morphological differences in the three subcortical structures. Afterward, the correlation analysis between surface morphological eigenvalues and cannabis usage characteristics was performed.
Compared with volumetric measures, the surface-based subcortical morphometry method detected more significant global morphological deformations in the left amygdala, right hippocampus, and right pallidum (overall-p < 0.05, corrected). More obvious morphological alterations (atrophy or expansion) were observed in specific subregions (vertex-based p-value<0.05, uncorrected) of the three subcortical structures. Both positive and negative subregional correlation areas were reported by the correlation analysis.
The current study illuminated new pathophysiologic mechanisms in the amygdala, hippocampus, and pallidum at the subregion level, which may inform the subsequent smaller-scale CB research.
•The surface-based morphometry method and MMS feature are sensitive to detecting regional morphological deformations of CB.•CB is accompanied by widespread morphological changes in specific subregions of the amygdala, hippocampus, and pallidum.•Positive and negative correlation areas of CB were detected by the correlation analysis in the three subcortical structures.
The purpose of this study was to ascertain the progress of recipients of research training in obstetrics and gynecology in establishing an active research career in academic medicine.
Existing data ...were used to examine the extent to which 41 individuals who had received American Association of Obstetricians and Gynecologists Foundation (AAOGF) fellowships had achieved outcomes indicative of a career in academic medicine. Outcomes included employment as a full-time faculty member, receipt of NIH research funding, number of publications, the types of journals in which these articles had appeared, and the type of research (eg, basic vs patient-oriented).
Among individuals who were awarded their fellowship between 1984 and 1997, 88% held faculty appointments, and 40% of these positions were in institutions that were more research-intensive that the medical degree–granting institutions of fellows. Slightly more than half of former fellows had successfully competed for NIH research funding, with 22% being awarded at least one R01 grant. Overall, fellows produced a total of 878 articles, one third of which appeared in clinical journals, 18% were in basic biomedical research journals, and 48% were in journals that published both types of research.
Previous AAOGF scholars have actively pursued research careers in academic obstetrics and gynecology. Their performance compares favorably with those of individuals receiving research training in other clinical specialties. A more complete understanding of their performance and the value added by the program would be possible if a core set of data on outcomes were available from other types of training efforts in both obstetrics and gynecology and other relevant disciplines.
Purpose/Objective: To compare the cognitive profiles of a well-characterized sample of adults with and without spinal cord injury (SCI) using the NIH Toolbox Cognition Battery NIHTB-CB. Research ...Method/Design: Participants were 156 community-dwelling individuals with SCI recruited from 3 academic medical centers, and 156 individuals without SCI selected from the NIHTB-CB normative database (N = 312). The main outcome measures were the demographically adjusted NIHTB-CB subtest and composite scores. Results: Individuals with and without SCI performed equivalently on the NIHTB-CB crystallized composite score, suggesting comparable premorbid functioning. Individuals with SCI produced lower scores on the NIHTB-CB fluid composite score by an average of 4.5 T-score points (Cohen's d = 0.50; a medium effect size). As a group, individuals with SCI had the most difficulty on tests of processing speed and executive functions, and some difficulty on a test of episodic memory, although effect sizes were small. These differences remained even after accounting for fine motor speed and dexterity. Individuals with tetraplegia produced lower scores than individuals with paraplegia on tests of processing speed and executive functioning. Conclusion/Implications: Community-dwelling individuals with SCI are at elevated risk of mild cognitive difficulties, particularly on tasks that rely on processing speed and executive functions. The NIHTB-CB is relatively brief, samples important cognitive domains, has good normative data, and is appropriate for some individuals with SCI (those who have functional use of one hand). The battery has standardized accommodations for individuals with minor motor limitations, but timed tests are inaccessible for individuals who are unable to perform rapid button presses.
Impact and Implications
Previous research on cognition after SCI has produced variable results. This variability is partially caused by normative data or control groups that are adjusted or matched for different factors. In this study, we used a cognitive battery in which each score is adjusted for the same demographic factors. This study supports previous findings that community-dwelling individuals with SCI have subtle deficits on tests of processing speed and executive functioning. Our results suggest that cognitive screening with community-dwelling individuals with SCI should target processing speed and executive functioning.
To investigate the roles of the cyclin D1/CDK4 and E2F-1/4 pathways and compare their work patterns in cell cycle changes induced by different doses of BaP.
Human embryo lung fibroblasts (HELFs) were ...treated with 2 μmol/L or 100 μmol/L BaP which were provided with some characteristics of transformed cells (T-HELFs). Cyclin D1, CDK4 and E2F-1/4 expressions were determined by Western blotting. Flow cytometry was used to detect the distribution of cell cycle.
After BaP treatment, the proportion of the first gap (G1) phase cells decreased. CDK4 and E2F-4 expression did not change significantly. In 2 μmol/L treated cells, a marked overexpression of cyclin D1 and E2F-1 was observed. However, in T-HELFs overexpression was limited to cyclin D1 only, and no overexpression of E2F-1 was observed. The decreases of G1 phase in response to BaP treatment were blocked in antisense cyclin D1 and antisense CDK4 transfected HELFs (A-D1 and A-K4) and T-HELFs (T-A-D1 and T-A-K4). After 2 μmol/L BaP treatment, overexpression of E2F-1 was attenuated in A-D1, and E2F-4 expression was decreased significantly in A-K4. In T-A-D1 and T-A-K4, E2F-4 expression was increased significantly, compared with T-HELFs. The E2F-1 expression remained unchanged in T-A-D1 and T-A-K4.
Cyclin D1/CDK4-E2F-1/4 pathways work in different patterns in response to low dose and high dose BaP treatment. In HELFs treated with 2 μmol/L BaP, cyclin D1 positively regulates the E2F-1 expression while CDK4 negatively regulates the E2F-4 expression; however, in HELFs treated with 100 μmol/L BaP, both cyclin D1 and CDK4 negatively regulate the E2F-4 expression.
Objective: The association between demographic characteristics and neurocognitive performance is well established; however, clinicians may have difficulty selecting when to use uncorrected versus ...demographically corrected scores. We compared these score types in individuals with traumatic brain injury (TBI) and stroke, on the National Institutes of Health Toolbox-Cognition Battery (NIHTB-CB). Research Method: Adults with TBI and stroke were demographically matched to controls, and completed the NIHTB-CB. Published "corrected scores" are adjusted for age, education, sex, and race/ethnicity; "uncorrected scores" were created using census data to represent the average adult in the U.S. population. Results: Effect sizes for the TBI and stroke groups versus controls were larger using corrected scores compared with uncorrected scores for the fluid composite (uncorrected to corrected effect sizes: TBI: d = 0.66, p < .001 to 0.83, p < .001; stroke d = 0.97, p < .001 to 1.10, p < .001). For the crystallized composite, effect sizes for the TBI and stroke groups versus controls were smaller and nonsignificant using corrected scores (uncorrected to corrected effect sizes: TBI d = 0.23, p = .03 to 0.20, p = .06; stroke d = 0.40, p < .001 to 0.17, p = .09). In the injury groups, demographic characteristics accounted for up to 33% of variance in uncorrected scores (p < .001), but <5% of variance in corrected scores (p > .06). Conclusions: Corrected scores were more sensitive to neurocognitive impairments in the brain-injured groups. Corrected scores have the advantage of controlling for variance associated with premorbid factors rather than changes in neurological functioning; are more helpful in characterizing acquired neurocognitive changes; and can aid in the interpretation of test performance.
Impact and Implications
This article extends previous research comparing demographically corrected and uncorrected scores from the National Institutes of Health Toolbox-Cognition Battery (NIHT-CB) with traumatic brain injury (TBI) and stroke populations, and demonstrates the increased construct validity of the NIHT-CB for classifying injury severity when using demographically corrected versus uncorrected fluid composite scores. This article highlights the importance of factoring out unwanted variance associated with patient demographic characteristics (e.g., age, education, gender, etc.) when interpreting the impact of acquired brain injury. In clinical practice, knowing when to use demographically corrected scores versus uncorrected scores is important for interpreting a patient's performance on neuropsychological testing and can assist clinicians in treatment planning by providing a more accurate reflection of current cognitive functioning by removing test variance associated with demographic characteristics. This article demonstrates that NIHTB-CB crystallized composite scores may serve as a measure of premorbid functioning, as it was relatively resistant to the deleterious effects of acquired brain injury.
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