Challenging the Conventional Interpretation of HCMV Seronegativity.
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ABSTRACT:
SUBMITTER: Waters S
PROVIDER: S-EPMC8626044 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The carboxysome is a giant protein complex that acts as a metabolic organelle in cyanobacteria and some chemoautotrophs. Its outer structure is formed by the assembly of thousands of copies of hexameric shell protein subunits into a molecular layer. The structure determination of a CcmK1 shell protein mutant (L11K) from the ?-carboxysome of the cyanobacterium Synechocystis PCC6803 led to challenges in structure determination. Twinning, noncrystallographic symmetry and packing of hexameric units in a special arrangement led to initial difficulties in space-group assignment. The correct space group was clarified after initial model refinement revealed additional symmetry. This study provides an instructive example in which broken symmetry requires a new choice of unit-cell origin in order to identify the highest symmetry space group. An additional observation related to the packing arrangement of molecules in this crystal suggests that these hexameric shell proteins might have lower internal symmetry than previously believed.
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Project description:BackgroundInstrumental variable (IV) methods are often used to identify 'local' causal effects in a subgroup of the population of interest. Such 'local' effects may not be ideal for informing clinical or policy decision making. When the instrument is non-causal, additional difficulties arise for interpreting 'local' effects. Little attention has been paid to these difficulties, even though commonly proposed instruments in epidemiology are non-causal (e.g. proxies for physician's preference; genetic variants in some Mendelian randomization studies).MethodsFor IV estimates obtained from both causal and non-causal instruments under monotonicity, we present results to help investigators pose four questions about the local effect estimates obtained in their studies. (1) To what subgroup of the population does the effect pertain? Can we (2) estimate the size of or (3) describe the characteristics of this subgroup relative to the study population? (4) Can the sensitivity of the effect estimate to deviations from monotonicity be quantified?ResultsWe show that the common interpretations and approaches for answering these four questions are generally only appropriate in the case of causal instruments.ConclusionsAppropriate interpretation of an IV estimate under monotonicity as a 'local' effect critically depends on whether the proposed instrument is causal or non-causal. The results and formal proofs presented here can help in the transparent reporting of IV results and in enhancing the use of IV estimates in informing decision-making efforts.
| S-EPMC6124612 | biostudies-literature
Project description:The aim was to elucidate how steps in drug translocation by a solute carrier transporter impact Michaelis-Menten parameters Km, Ki, and Vmax. The first objective was to derive a model for carrier-mediated substrate translocation and perform sensitivity analysis with regard to the impact of individual microrate constants on Km, Ki, and Vmax. The second objective was to compare underpinning microrate constants between compounds translocated by the same transporter. Equations for Km, Ki, and Vmax were derived from a six-state model involving unidirectional transporter flipping and reconfiguration. This unidirectional model is applicable to co-transporter type solute carriers, like the apical sodium-dependent bile acid transporter (ASBT) and the proton-coupled peptide cotransporter (PEPT1). Sensitivity analysis identified the microrate constants that impacted Km, Ki, and Vmax. Compound comparison using the six-state model employed regression to identify microrate constant values that can explain observed Km and Vmax values. Results yielded some expected findings, as well as some unanticipated effects of microrate constants on Km, Ki, and Vmax. Km and Ki were found to be equal for inhibitors that are also substrates. Additionally, microrate constant values for certain steps in transporter functioning influenced Km and Vmax to be low or high.
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Project description:BackgroundThe benefits of minimally invasive surgery (MIS) for low-risk or minor liver resection are well established. There is growing interest in MIS for major hepatectomy (MH) and other challenging resections, but there remain unanswered questions of safety that prevent broad adoption of this technique.Study designWe conducted a retrospective cohort study of patients undergoing hepatectomy at 65 hospitals participating in the NSQIP Hepatopancreatobiliary Collaborative in 2014. We assessed serious morbidity or mortality (SMM; including organ/space infection and organ failure). Secondary outcomes included transfusion, bile leak, liver failure, reoperation or intervention, and 30-day readmission. We also measured factors considered to make resection more challenging (ie large tumors, cirrhosis, ≥3 concurrent resections, previous neoadjuvant chemotherapy, and morbid obesity).ResultsThere were 2,819 patients who underwent hepatectomy (aged 58 ± 14 years; 53% female; 25% had MIS). After adjusting for clinical and operative factors, the odds of SMM (odds ratio [OR] = 0.57; 95% CI 0.34 to 0.96; p = 0.03) and reoperation or intervention (OR = 0.52; 95% CI 0.29 to 0.93; p = 0.03) were significantly lower for patients undergoing MIS compared with open. In the MH group (n = 1,015 [13% MIS]), there was no difference in the odds of SMM after MIS (OR = 0.37; 95% CI 0.13 to 1.11; p = 0.08); however, minimally invasive MH met criteria for noninferiority. There were no differences in liver-specific complications or readmission between the groups. Odds of SMM were significantly lower after MIS among patients who had received neoadjuvant chemotherapy (OR = 0.33; 95% CI 0.15 to 0.70; p = 0.004).ConclusionsIn this large study of minimally invasive MH, we found safety outcomes that are equivalent or superior to conventional open surgery. Although the decision to offer MIS might be influenced by factors not included in this evaluation (eg surgeon experience and other patient factors), these findings support its current use in MH.
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Project description:Although copy number alterations (CNAs) and translocations constitute the backbone of the diagnosis and prognostication of acute myeloid leukemia (AML), techniques used for their assessment in routine diagnostics have not been reconsidered for decades. We used a combination of 2 next-generation sequencing-based techniques to challenge the currently recommended conventional cytogenetic analysis (CCA), comparing the approaches in a series of 281 intensively treated patients with AML. Shallow whole-genome sequencing (sWGS) outperformed CCA in detecting European Leukemia Net (ELN)-defining CNAs and showed that CCA overestimated monosomies and suboptimally reported karyotype complexity. Still, the concordance between CCA and sWGS for all ELN CNA-related criteria was 94%. Moreover, using in silico dilution, we showed that 1 million reads per patient would be enough to accurately assess ELN-defining CNAs. Total genomic loss, defined as a total loss ≥200 Mb by sWGS, was found to be a better marker for genetic complexity and poor prognosis compared with the CCA-based definition of complex karyotype. For fusion detection, the concordance between CCA and whole-transcriptome sequencing (WTS) was 99%. WTS had better sensitivity in identifying inv(16) and KMT2A rearrangements while showing limitations in detecting lowly expressed PML-RARA fusions. Ligation-dependent reverse transcription polymerase chain reaction was used for validation and was shown to be a fast and reliable method for fusion detection. We conclude that a next-generation sequencing-based approach can replace conventional CCA for karyotyping, provided that efforts are made to cover lowly expressed fusion transcripts.
| S-EPMC7903223 | biostudies-literature
Project description:TP53 variant interpretation is still challenging, especially in patients with attenuated Li-Fraumeni syndrome (LFS). We investigated the prevalence of pathogenic/likely pathogenic (P/LP) variants and LFS disease in the Hungarian population of cancer patients. By testing 893 patients with multiplex or familial cancer, we identified and functionally characterized novel splice variants of TP53 helping accurate variant classification. The differences among various semi-automated interpretation platforms without manual curation highlight the importance of focused interpretation as the automatic classification systems do not apply the TP53-specific criteria. The predicted frequency of the TP53 P/LP variants in Hungary is 0.3 per million which most likely underestimates the real prevalence. The higher detection rate of disease-causing variants in patients with attenuated LFS phenotype compared to the control population (OR 12.5; p < 0.0001) may raise the potential benefit of the TP53 genetic testing as part of the hereditary cancer panels of patients with multiple or familial cancer even when they do not meet Chompret criteria. Tumours developed at an earlier age in phenotypic LFS patients compared to the attenuated LFS patients which complicates genetic counselling as currently there are no different recommendations in surveillance protocols for LFS, phenotypic LFS, and attenuated LFS patients.
| S-EPMC10471726 | biostudies-literature
Project description:Differentiated vulvar intraepithelial neoplasia (dVIN) is a premalignant lesion that is known to progress rapidly to invasive carcinoma. Accurate histological diagnosis is therefore crucial to allow appropriate treatment. To identify reliable diagnostic features, we evaluated the inter-observer agreement in the histological assessment of dVIN, among a bi-national, multi-institutional group of pathologists. Two investigators from Erasmus MC selected 36 hematoxylin-eosin-stained glass slides of dVIN and no-dysplasia, and prepared a list of 15 histological features of dVIN. Nine participating pathologists (i) diagnosed each slide as dVIN or no-dysplasia, (ii) indicated which features they used for the diagnosis, and (iii) rated these features in terms of their diagnostic usefulness. Diagnoses rendered by > 50% participants were taken as the consensus (gold standard). p53-immunohistochemistry (IHC) was performed for all cases, and the expression patterns were correlated with the consensus diagnoses. Kappa (ĸ)-statistics were computed to measure inter-observer agreements, and concordance of the p53-IHC patterns with the consensus diagnoses. For the diagnosis of dVIN, overall agreement was moderate (ĸ = 0.42), and pair-wise agreements ranged from slight (ĸ = 0.10) to substantial (ĸ = 0.73). Based on the levels of agreement and ratings of usefulness, the most helpful diagnostic features were parakeratosis, cobblestone appearance, chromatin abnormality, angulated nuclei, atypia discernable under × 100, and altered cellular alignment. p53-IHC patterns showed substantial concordance (ĸ = 0.67) with the consensus diagnoses. Histological interpretation of dVIN remains challenging with suboptimal inter-observer agreement. We identified the histological features that may facilitate the diagnosis of dVIN. For cases with a histological suspicion of dVIN, consensus-based pathological evaluation may improve the reliability of the diagnosis.
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Project description:Human cytomegalovirus (HCMV), a member of the herpesvirus family, is a large complex enveloped virus composed of both viral and cellular gene products. While the sequence of the HCMV genome has been known for over a decade, the full set of viral and cellular proteins that compose the HCMV virion are unknown. To approach this problem we have utilized gel-free two-dimensional capillary liquid chromatography-tandem mass spectrometry (MS/MS) and Fourier transform ion cyclotron resonance MS to identify and determine the relative abundances of viral and cellular proteins in purified HCMV AD169 virions and dense bodies. Analysis of the proteins from purified HCMV virion preparations has indicated that the particle contains significantly more viral proteins than previously known. In this study, we identified 71 HCMV-encoded proteins that included 12 proteins encoded by known viral open reading frames (ORFs) previously not associated with virions and 12 proteins from novel viral ORFs. Analysis of the relative abundance of HCMV proteins indicated that the predominant virion protein was the pp65 tegument protein and that gM rather than gB was the most abundant glycoprotein. We have also identified over 70 host cellular proteins in HCMV virions, which include cellular structural proteins, enzymes, and chaperones. In addition, analysis of HCMV dense bodies indicated that these viral particles are composed of 29 viral proteins with a reduced quantity of cellular proteins in comparison to HCMV virions. This study provides the first comprehensive quantitative analysis of the viral and cellular proteins that compose infectious particles of a large complex virus.
| S-EPMC521840 | biostudies-literature
Project description:A substantial proportion of pathogenic variants associated with an increased risk of hereditary cancer are sequence variants affecting RNA splicing. The classification of these variants can be complex when both non-functional and functional transcripts are produced from the variant allele. We present four BRCA2 splice site variants with complex variant interpretations (BRCA2 c.68-3T>G, c.68-2A>G, c.425G>T, c.8331+2T>C). Evidence supporting a pathogenic classification is available for each variant, including in silico models, absence in population databases, and published functional data. However, comprehensive RNA analysis showed that some functional transcript may be produced by each variant. BRCA2 c.68-3T>G results in a partial splice defect. For BRCA2 c.68-2A>G and c.425G>T, aberrant splicing was shown to produce a potentially functional, in-frame transcript. BRCA2 c.8331+2T>C may utilize a functional GC donor in place of the wild-type GT donor. The severity of cancer history for carriers of these variants was also assessed using a history weighting algorithm and was not consistent with pathogenic controls (carriers of known pathogenic variants in BRCA2). Due to the conflicting evidence, our laboratory classifies these BRCA2 variants as variants of uncertain significance. This highlights the importance of evaluating new and existing evidence to ensure accurate variant classification and appropriate patient care.
| S-EPMC8799590 | biostudies-literature
Project description:ObjectivesTo evaluate if computer-aided diagnosis (CAD) prior to prostate multi-parametric MRI (mpMRI) can improve sensitivity and agreement between radiologists.MethodsNine radiologists (three each high, intermediate, low experience) from eight institutions participated. A total of 163 patients with 3-T mpMRI from 4/2012 to 6/2015 were included: 110 cancer patients with prostatectomy after mpMRI, 53 patients with no lesions on mpMRI and negative TRUS-guided biopsy. Readers were blinded to all outcomes and detected lesions per PI-RADSv2 on mpMRI. After 5 weeks, readers re-evaluated patients using CAD to detect lesions. Prostatectomy specimens registered to MRI were ground truth with index lesions defined on pathology. Sensitivity, specificity and agreement were calculated per patient, lesion level and zone-peripheral (PZ) and transition (TZ).ResultsIndex lesion sensitivity was 78.2% for mpMRI alone and 86.3% for CAD-assisted mpMRI (p = 0.013). Sensitivity was comparable for TZ lesions (78.7% vs 78.1%; p = 0.929); CAD improved PZ lesion sensitivity (84% vs 94%; p = 0.003). Improved sensitivity came from lesions scored PI-RADS < 3 as index lesion sensitivity was comparable at PI-RADS ≥ 3 (77.6% vs 78.1%; p = 0.859). Per patient specificity was 57.1% for CAD and 70.4% for mpMRI (p = 0.003). CAD improved agreement between all readers (56.9% vs 71.8%; p < 0.001).ConclusionsCAD-assisted mpMRI improved sensitivity and agreement, but decreased specificity, between radiologists of varying experience.Key points• Computer-aided diagnosis (CAD) assists clinicians in detecting prostate cancer on MRI. • CAD assistance improves agreement between radiologists in detecting prostate cancer lesions. • However, this CAD system induces more false positives, particularly for less-experienced clinicians and in the transition zone. • CAD assists radiologists in detecting cancer missed on MRI, suggesting a path for improved diagnostic confidence.
| S-EPMC8023433 | biostudies-literature