Tag: nevin manimala

Proc Natl Acad Sci U S A. 2021 Jul 20;118(29):e2104013118. doi: 10.1073/pnas.2104013118.

ABSTRACT

Somatic hypermutation (SHM) and class-switch recombination (CSR) of the immunoglobulin (Ig) genes allow B cells to make antibodies that protect us against a wide variety of pathogens. SHM is mediated by activation-induced deaminase (AID), occurs at a million times higher frequency than other mutations in the mammalian genome, and is largely restricted to the variable (V) and switch (S) regions of Ig genes. Using the Ramos human Burkitt’s lymphoma cell line, we find that H3K79me2/3 and its methyltransferase Dot1L are more abundant on the V region than on the constant (C) region, which does not undergo mutation. In primary naïve mouse B cells examined ex vivo, the H3K79me2/3 modification appears constitutively in the donor Sμ and is inducible in the recipient Sγ1 upon CSR stimulation. Knockout and inhibition of Dot1L in Ramos cells significantly reduces V region mutation and the abundance of H3K79me2/3 on the V region and is associated with a decrease of polymerase II (Pol II) and its S2 phosphorylated form at the IgH locus. Knockout of Dot1L also decreases the abundance of BRD4 and CDK9 (a subunit of the P-TEFb complex) on the V region, and this is accompanied by decreased nascent transcripts throughout the IgH gene. Treatment with JQ1 (inhibitor of BRD4) or DRB (inhibitor of CDK9) decreases SHM and the abundance of Pol II S2P at the IgH locus. Since all these factors play a role in transcription elongation, our studies reinforce the idea that the chromatin context and dynamics of transcription are critical for SHM.

PMID:34253616 | DOI:10.1073/pnas.2104013118

J Neurosci. 2021 Jul 12:JN-RM-2137-20. doi: 10.1523/JNEUROSCI.2137-20.2021. Online ahead of print.

ABSTRACT

In everyday life, we have no trouble categorizing objects varying in position, size, and orientation. Previous fMRI research shows that higher-level object processing regions in the human lateral occipital cortex may link object responses from different affine states (i.e. size and viewpoint) through a general linear mapping function capable of predicting responses to novel objects. In this study, we extended this approach to examine the mapping for both Euclidean (e.g. position and size) and non-Euclidean (e.g. image statistics and spatial frequency) transformations across the human ventral visual processing hierarchy, including areas V1, V2, V3, V4, ventral occipitotemporal cortex (VOT), and lateral occipitotemporal cortex (LOT). The predicted pattern generated from a linear mapping function could capture a significant amount of the changes associated with the transformations throughout the ventral visual stream. The derived linear mapping functions were not category independent, as performance was better for the categories included than those not included in training and better between two similar versus two dissimilar categories in both lower and higher visual regions. Consistent with object representations being stronger in higher than lower visual regions, pattern selectivity and object category representational structure were somewhat better preserved in the predicted patterns in higher than lower visual regions. There were no notable differences between Euclidean and non-Euclidean transformations. These findings demonstrate a near-orthogonal representation of object identity and these non-identity features throughout the human ventral visual processing pathway, with these non-identity features largely untangled from the identity features early in visual processing.Significance StatementPresently we still do not fully understand how object identity and non-identity (e.g. position, size) information are simultaneously represented in the primate ventral visual system to form invariant representations. Previous work suggests that the human lateral occipital cortex may be linking different affine states of object representations through general linear mapping functions. Here we show that across the entire human ventral processing pathway, we could link object responses in different states of non-identity transformations through linear mapping functions for both Euclidean and non-Euclidean transformations. These mapping functions are not identity-independent, suggesting that object identity and non-identity features are represented in a near, rather than a completely, orthogonal manner.

PMID:34253629 | DOI:10.1523/JNEUROSCI.2137-20.2021

Clin Cancer Res. 2021 Jul 12:clincanres.CCR-21-2051-E.2021. doi: 10.1158/1078-0432.CCR-21-2051. Online ahead of print.

ABSTRACT

PURPOSE: The Cancer Immune Monitoring and Analysis Centers – Cancer Immunologic Data Commons (CIMAC-CIDC) network supported by the NCI Cancer Moonshot initiative was established to provide correlative analyses for clinical trials in cancer immunotherapy, using state-of-the-art technology. Fundamental to this initiative is implementation of multiplex immunohistochemical assays to define the composition and distribution of immune infiltrates within tumors in the context of their potential role as biomarkers. A critical unanswered question involves the relative fidelity of such assays to reliably quantify tumor associated immune cells across different platforms.

EXPERIMENTAL DESIGN: Three CIMAC sites compared across their laboratories: 1) image analysis algorithms, 2) image acquisition platforms, 3) multiplex staining protocols. Two distinct high-dimensional approaches were employed: multiplexed immunohistochemical consecutive staining on single slide (MICSSS) and multiplexed immunofluorescence (mIF). To eliminate variables potentially impacting assay performance, we completed a multistep harmonization process, first comparing assay performance using independent protocols followed by the integration of laboratory-specific protocols and finally, validating this harmonized approach in an independent set of tissues.

RESULTS: Data generated at the final validation step showed an inter-site Spearman correlation coefficient of {greater than or equal to}0.85 for each marker within and across tissue types, with an overall low average coefficient of variation {less than or equal to}0.1.

CONCLUSIONS: Our results support interchangeability of protocols and platforms to deliver robust, and comparable data using similar tissue specimens and confirm that CIMAC-CIDC analyses may therefore be used with confidence for statistical associations with clinical outcomes largely independent of site, antibody selection, protocol, and platform across different sites.

PMID:34253580 | DOI:10.1158/1078-0432.CCR-21-2051

Med Humanit. 2021 Jul 12:medhum-2021-012156. doi: 10.1136/medhum-2021-012156. Online ahead of print.

ABSTRACT

COVID-19 represents one of the most challenging global health issues in modern times. However, as epidemics have affected humans since our origins, many before us have described how significantly they compromise human lives. Leaving apart the aspects more linked to medicine and health sciences, we focus here on analysing how epidemics force people to change their habits, what type of emotions and behaviours they promote, and which roles are played by different social actors. For such a purpose, especially if we wish to draw some parallels between past epidemics and COVID-19, historical records seemed to be more suitable than literary works. Nonetheless, we have taken this approach relying on La Peste (Albert Camus, 1947), a novel based on a fictional epidemic of plague in the Algerian town of Oran. Far from creating a barrier separating fiction from reality, this reading allowed us to establish several links with our current situation. Recognising that context and solutions vary widely between the two scenarios, core matters concerning epidemics seemed to remain invariable. The important role of data and statistics, the leadership acquired by health authorities, the separations of relatives or the negative effects on trade and business are some issues which took place in Oran as well as nowadays. Besides that, epidemics also affect humans at an individual level, and certain thoughts and feelings in La Peste‘s main characters may make us identify with our own fears and desires.

PMID:34253585 | DOI:10.1136/medhum-2021-012156

Cardiovasc Revasc Med. 2021 Jun 25:S1553-8389(21)00488-7. doi: 10.1016/j.carrev.2021.06.123. Online ahead of print.

ABSTRACT

BACKGROUND: Most pivotal transcatheter aortic valve replacement (TAVR) trials have excluded patients with bicuspid aortic stenosis (AS). This study compared TAVR in low-risk patients with bicuspid AS to those with tricuspid AS, incorporating data from prospective trials.

METHODS: We selected prospective US low-risk TAVR trials containing a bicuspid arm for this meta-analysis, examining outcomes at 30 days. Study results were pooled using a hierarchical Bayesian random-effects model.

RESULTS: Included were 3 Food and Drug Administration (FDA)-approved investigational device exemption (IDE) trials that enrolled a total of 1810 low-risk patients with symptomatic severe AS for TAVR. We compared 380 bicuspid patients with 1430 tricuspid patients. Event rates at 30 days overall were low, with similar mortality (odds ratio [OR], 0.38; 95% credible interval [CrI]: 0.08, 1.78; I², 0%), non-disabling stroke (OR, 0.45; 95% CrI: 0.15, 1.07; I², 9%), and permanent pacemaker implantation (OR, 0.86; 95% CrI: 0.41, 1.47; I², 59%). There were statistically significant differences in disabling stroke (OR, 0.16; 95% CrI: 0.01, 0.90; I², NA) and coronary obstruction (OR, 0.21; 95% CrI: 0.05, 0.91) that disappeared after sensitivity analysis by adding a single event to the tricuspid arm. Hemodynamics were similar at 30 days.

CONCLUSIONS: Preliminary data from the FDA-approved IDE trials of low-risk patients with bicuspid AS undergoing TAVR demonstrated 30-day outcomes comparable to low-risk tricuspid patients, except for a trend toward higher stroke in bicuspid patients. Randomized trials are warranted to reassure the safety and long-term outcome of TAVR in patients with severe bicuspid AS.

PMID:34253474 | DOI:10.1016/j.carrev.2021.06.123

J Plast Reconstr Aesthet Surg. 2021 Jun 9:S1748-6815(21)00291-6. doi: 10.1016/j.bjps.2021.05.039. Online ahead of print.

ABSTRACT

INTRODUCTION: The Breast Reconstruction Risk Assessment (BRA) Score tool is a risk calculator developed to predict the risk of complications in individual patients undergoing breast reconstruction. It was developed in a North American population exclusively undergoing immediate breast reconstruction. This study sought to assess the predictions of the BRA Score tool against the measured outcomes of surgery for an Australian public hospital population, including both immediate and delayed reconstructions.

METHOD: This was a retrospective cohort study of data from women at a single Australian public teaching hospital unit. Data from the Flinders Breast Reconstruction Database was retrieved and compared to BRA Scores calculated for each patient. Receiver operating curve area under the curve analysis was performed as well as Brier scores to compare predicted versus observed complications.

RESULTS: BRA Score predictions were reasonable or good (C-statistic >0.7, Brier score <0.09) for the complications of overall surgical complications, surgical site infection (SSI) and seroma at 30 days, and similarly accurate for prediction of the same complications for implant reconstructions at 12 months. There were similar findings between delayed and immediate reconstructions.

CONCLUSION: The BRA Score risk calculator is valid to detect some risks in both patients undergoing immediate and delayed breast reconstruction in an Australian public hospital setting. SSI is the best predicted complication and is well-predicted across both autologous and prosthetic reconstruction types.

PMID:34253489 | DOI:10.1016/j.bjps.2021.05.039

Disabil Health J. 2021 Jul 7:101170. doi: 10.1016/j.dhjo.2021.101170. Online ahead of print.

ABSTRACT

BACKGROUND: Little is known about the exposure of youth with disability to cyber victimisation.

OBJECTIVE: /Hypothesis: To estimate the prevalence of peer cyber and non-cyber victimisation in a nationally representative sample of 14-year-old adolescents with and without disability and to determine whether gender moderates the relationship between disability and exposure to victimisation.

METHODS: Secondary analysis of data collected in Wave 6 of the UK’s Millennium Cohort Survey on 11,726 14-year-old adolescents living in the UK.

RESULTS: Adolescents with disability had higher prevalence of cyber and non-cyber victimisation than those with no disability. For cyber victimisation there was a statistically significant interaction between gender and disability, with evidence of increased cyber victimisation for adolescents with disability compared to those with no disability among girls, but not boys. For non-cyber victimisation there was no evidence of an interaction between gender and disability.

CONCLUSIONS: The prevalence of both cyber and non-cyber victimisation was higher among adolescents with disability than those with no disability. The association between disability and risk of exposure to peer cyber victimisation appears to be moderated by gender.

PMID:34253505 | DOI:10.1016/j.dhjo.2021.101170

Reprod Biomed Online. 2021 May 2:S1472-6483(21)00195-4. doi: 10.1016/j.rbmo.2021.04.019. Online ahead of print.

ABSTRACT

RESEARCH QUESTION: Is transvaginal hydrolaparoscopy (THL) non-inferior to hysterosalpingography (HSG) as a first-line tubal patency test in subfertile women in predicting the chance of conception leading to live birth?

DESIGN: A multicentre, randomized controlled trial in four teaching hospitals in the Netherlands, which randomized subfertile women scheduled for tubal patency testing to either THL or HSG as a first-line tubal patency test. The primary outcome was conception leading to live birth within 24 months after randomization.

RESULTS: A total of 149 women were randomized to THL and 151 to HSG. From the intention-to-treat population, 83 women from the THL group (58.5%) conceived and delivered a live born child within 24 months after randomization compared with 82 women (55.4%) in the HSG group (difference 3.0%, 95% CI -8.3 to 14.4). Time to conception leading to live birth was not statistically different between groups. Miscarriage occurred in 16 (11.3%) women in the THL group, versus 20 (13.5%) women in the HSG group (RR = 0.66, 95% CI 0.34 to 1.32, P = 0.237), and multiple pregnancies occurred in 12 (8.4%) women in the THL group compared with 19 (12.8%) women in the HSG group (RR = 0.84, 95% CI 0.46 to 1.55, P = 0.58). Ectopic pregnancy was diagnosed in two women in the HSG group (1.4%) and none in the THL group (P = 0.499).

CONCLUSION: In a preselected group of subfertile women with a low risk of tubal pathology, use of THL was not inferior to HSG as a first-line test for predicting conception leading to live birth.

PMID:34253451 | DOI:10.1016/j.rbmo.2021.04.019

Eur J Intern Med. 2021 Jul 10:S0953-6205(21)00242-9. doi: 10.1016/j.ejim.2021.06.031. Online ahead of print.

ABSTRACT

BACKGROUND: Interactions between chronic kidney disease (CKD) and several comorbidities may potentially affect prognosis of older hospitalized patients. This study aims at evaluating the prognostic interactions between estimated glomerular filtration rate (eGFR), anemia, sarcopenia, functional and cognitive dysfunction, and 3-year mortality among older patients discharged from acute care hospitals.

METHODS: Our series consisted of 504 older adults enrolled in a multicenter observational study carried out in twelve Acute Geriatric and Internal Medicine wards throughout Italy. CKD was defined as an eGFR< 60 ml/min/1.73 m². Anemia, Short Portable Status Mental Questionnaire (SPMSQ), Basic Activities of Daily Living (BADL), sarcopenia, and Charlson index were considered in the analysis. 3-year survival was investigated by Cox regression and prognostic interactions among study variables were assessed by survival tree analysis. Accuracy of different survival models was investigated by C-index.

RESULTS: eGFR < 30 mL/min/1.73 m², anemia, sarcopenia, SPMSQ ≥ 5, and impairment in 1 or more BADL were significantly associated with mortality. Survival tree analysis showed that patients with eGFR < 35.32 ml/min/1.73 m² and SPMSQ ≥ 5 had the highest risk of mortality [hazard ratio (HR): 5.49, 95%CI: 3.04-9.94] followed by those with eGFR < 35.32 ml/min/1.73 m², hemoglobin < 11.95 g/dL and SPMSQ < 5 (HR:3.65; 95%CI: 2.21-6.02) and those with eGFR 35.32-47.99 ml/min/1.73 m² and sarcopenia (HR:3.65; 95%CI: 1.99-6.69). Survival tree leaf node membership had good accuracy in predicting the study outcome (C-index: 0.73, 95%CI:0.70-0.76).

CONCLUSIONS: Interactions among study risk factors designed distinct risk profiles in older patients discharged from acute care hospitals, that may help identify patients needing targeted interventions and appropriate follow-up after discharge.

PMID:34253448 | DOI:10.1016/j.ejim.2021.06.031

Bioinformatics. 2021 Jul 12;37(Supplement_1):i42-i50. doi: 10.1093/bioinformatics/btab336.

ABSTRACT

MOTIVATION: Anti-cancer drug sensitivity prediction using deep learning models for individual cell line is a significant challenge in personalized medicine. Recently developed REFINED (REpresentation of Features as Images with NEighborhood Dependencies) CNN (Convolutional Neural Network)-based models have shown promising results in improving drug sensitivity prediction. The primary idea behind REFINED-CNN is representing high dimensional vectors as compact images with spatial correlations that can benefit from CNN architectures. However, the mapping from a high dimensional vector to a compact 2D image depends on the a priori choice of the distance metric and projection scheme with limited empirical procedures guiding these choices.

RESULTS: In this article, we consider an ensemble of REFINED-CNN built under different choices of distance metrics and/or projection schemes that can improve upon a single projection based REFINED-CNN model. Results, illustrated using NCI60 and NCI-ALMANAC databases, demonstrate that the ensemble approaches can provide significant improvement in prediction performance as compared to individual models. We also develop the theoretical framework for combining different distance metrics to arrive at a single 2D mapping. Results demonstrated that distance-averaged REFINED-CNN produced comparable performance as obtained from stacking REFINED-CNN ensemble but with significantly lower computational cost.

AVAILABILITY AND IMPLEMENTATION: The source code, scripts, and data used in the paper have been deposited in GitHub (https://github.com/omidbazgirTTU/IntegratedREFINED).

SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

PMID:34252971 | DOI:10.1093/bioinformatics/btab336