scholarly journals A Massively Parallel Trafficking Assay Accurately Predicts Loss of Channel Function in KCNH2 Variants

2021 ◽  
Author(s):  
Chai Ann Ng ◽  
Rizwan Ullah ◽  
Jessica Farr ◽  
Adam P Hill ◽  
Krystian A Kozek ◽  
...  
Keyword(s):  
Current Density ◽  
Clinical Decision Making ◽  
Clinical Decision ◽  
Massively Parallel ◽  
Single Nucleotide Variants ◽  
Exon 2 ◽  
Tail Current ◽  
Missense Variants ◽  
Channel Function ◽  
Variant Information

High throughput genomics has greatly facilitated identification of genetic variants. However, determining which variants contribute to disease causation is challenging with more than half of all missense variants now classified as variants of uncertain significance (VUS). A VUS leaves patients and their clinicians unable to utilize the variant information in clinical decision-making. In long QT syndrome type 2, KCNH2 channel function is directly associated with disease presentation. Therefore, functional phenotyping of KCNH2 variants can provide direct evidence to aid variant classification. Here, we investigated the expression of all codon variants in exon 2 of KCNH2 using a massively parallel trafficking assay and for a subset of 458 single nucleotide variants compared the results with peak tail current density and gating using automated patch clamp electrophysiology. Trafficking could correctly classify loss of peak tail current density variants with an AUC reaching 0.94 compared to AUCs of 0.75 to 0.8 for in silico variant classifiers. We suggest massively parallel trafficking assays can provide prospective and accurate functional assessment for all missense variants in KCNH2 and most likely many other ion channels and membrane proteins.

scholarly journals Effect sizes of somatic mutations in cancer

2017 ◽  
Author(s):  
Vincent L. Cannataro ◽  
Stephen G. Gaffney ◽  
Jeffrey P. Townsend
Keyword(s):  
Cancer Biology ◽  
Clinical Decision Making ◽  
Basic Research ◽  
Clinical Decision ◽  
Braf V600e ◽  
Effect Sizes ◽  
Relative Importance ◽  
Single Nucleotide Variants ◽  
Driver Genes ◽  
Tumor Boards

ABSTRACTA major goal of cancer biology is determination of the relative importance of the genomic alterations that confer selective advantage to cancer cells. Tumor sequence surveys have frequently ranked the importance of substitutions to cancer growth by P value or a false-discovery conversion thereof. However, P values are thresholds for belief, not metrics of effect. Their frequent misuse as metrics of effect has often been vociferously decried. Here, we estimate the effect sizes of all recurrent single nucleotide variants in 23 cancer types, quantifying relative importance within and between driver genes. Some of the variants with the highest effect size, such as EGFR L858R in lung adenocarcinoma and BRAF V600E in primary skin cutaneous melanoma, have yielded remarkable therapeutic responses. Quantification of cancer effect sizes has immediate importance to the prioritization of clinical decision-making by tumor boards, selection and design of clinical trials, pharmacological targeting, and basic research prioritization.

scholarly journals Recent developments in the treatment of metastatic colorectal cancer

2017 ◽  
Vol 9 (8) ◽  
pp. 551-564 ◽  
Author(s):  
Jonathan M. Loree ◽  
Scott Kopetz
Keyword(s):  
Colorectal Cancer ◽  
Decision Making ◽  
Clinical Decision Making ◽  
Growth Factor Receptor ◽  
Low Frequency ◽  
Clinical Decision ◽  
Tumor Location ◽  
Targeted Agents ◽  
Braf Mutations ◽  
Exon 2

Over the past decade there have been significant advances in the molecular characterization of colorectal cancer (CRC) that are driving treatment decisions. Expanded RAS testing beyond KRAS exon 2 was established as crucial for identifying patients who will respond to anti-epidermal growth factor receptor (EGFR) therapies and low-frequency mutations in RAS/tumor heterogeneity are gaining recognition as potential mechanisms of resistance. Despite this progress, the fact that we do not understand why left-sided but not right-sided tumors have improved outcomes following anti-EGFR therapy highlights our superficial understanding of this disease. Even with few new targeted agents receiving approval in CRC, the incorporation of next-generation sequencing into clinical decision making represents an important step forward. Biomarkers such as BRAF mutations, microsatellite instability, and HER2 amplification represent promising molecular aberrations with therapies in various stages of development, and highlight the importance of companion diagnostics in supporting targeted agents. In this review, we will discuss the importance of incorporating biomarkers into clinical decision making and regimen selection in CRC. We will particularly focus on the recent evidence suggesting an important role for tumor location in selecting first-line therapy, the importance of recent advances in biomarker development and molecular subtyping, as well as recently approved agents (regorafenib and TAS-102) and promising targeted agents that have the potential to change the standard of care.

scholarly journals Genetic and Clinical Profiles of Pheochromocytoma and Paraganglioma: A Single Center Study

2020 ◽  
Vol 11 ◽  
Author(s):  
Xiaosen Ma ◽  
Ming Li ◽  
Anli Tong ◽  
Fen Wang ◽  
Yunying Cui ◽  
...  
Keyword(s):  
Sanger Sequencing ◽  
Clinical Decision Making ◽  
Clinical Decision ◽  
Exon 2 ◽  
Germline Variants ◽  
Pathogenic Variants ◽  
Pathogenic Genes ◽  
Single Center Study ◽  
Clinical Profiles ◽  
Generation Sequencing

Pheochromocytoma/paraganglioma (PPGL) has a high genetic heterogeneity with 40% germline variants in known pathogenic genes. Data in Chinese on this aspect are scanty. To detect the genetic and clinical profile of Chinese PPGL patients, we examined the variants of 12 known germline pathogenic genes (SDHA, SDHB, SDHC, SDHD, SDHAF2, FH, VHL, RET, NF1, MAX, TMEM127, and KIF1B) by next-generation sequencing and Sanger sequencing in 314 Chinese PPGL subjects. Twenty nine percent of Chinese PPGL patients had germline variants and SDHB was the most frequently mutated (14.6%). The most frequent SDHB variants were in exon 2, exon 7, and IVS 7. Pathogenic variants were more likely to occur in metastatic PPGL patients, paragangliomas, and patients under 30, with the ratio being 50.7% (35/69), 35.9% (56/156), and 49.5% (52/105), respectively. Our cohort included 314 patients from a single setting. The genetic and clinical features of Chinese PPGL patients were unique in some aspects compared to their non-Chinese counterparts. Identification of genotype-phenotype relation can serve as an effective tool for genetic prioritization and clinical decision-making.

Correlation of existence and number of mutations in DDR signaling pathway genes with poor survival after resection of colorectal liver metastases.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e16004-e16004
Author(s):  
Kun Wang ◽  
Hongwei Wang ◽  
Kemin Jin ◽  
Xiaoyu Zhang ◽  
Chunhe Yang ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Poor Prognosis ◽  
Clinical Decision Making ◽  
Gene Mutations ◽  
Clinical Decision ◽  
Copy Number Variations ◽  
Single Mutation ◽  
Wild Type ◽  
Single Nucleotide Variants ◽  
The Impact

e16004 Background: Patients of colorectal cancer with liver metastatic (CRLM) show various in recurrence and prognosis. Previous researches have revealed that the disfunction of DNA damage repair (DDR) signaling pathways was correlative with oncogenesis and poor prognosis. Here we aimed to determine the impact of DDR gene mutations on survival in patients undergoing CRLM resection. Methods: Tumor tissues from 164 patients with CRLM were collected for next generation sequencing (NGS). Single nucleotide variants, indels, and copy number variations were obtained from a 620-gene panel, including 68 genes in 7 DDR signaling pathways. Correlations of mutations in DDR genes with overall survival (OS) and recurrence-free survival (RFS) were determined by using Kaplan-Meier analysis. Results: 152/164 of patients carried at least one of DDR gene alternations. The most frequently mutated gene was TP53 (132/164), followed by CHEK2 (21/164), BRCA2 (10/164), ATM (9/164), PRKDC (8/164), FANCM (8/164), ATR (7/164), POLE (5/164), BRCA1 (4/164), POLD (3/164). Survival analysis indicated that TP53 mutations were not correlated with OS and RFS (P = 0.38 and 0.21). Further analysis in the TP53mut subgroup showed that the patients with other DDR gene mutations (64/132, 48.48%) exhibited a significantly worse OS than the wild type ones (P = 0.04). Especially, gene alternations involving in the Fanconi anemia (FA) pathway were significantly associated with worse OS and RFS (P = 0.0014 and 0.006). Interestingly, besides the TP53 mutation, patients carrying more than 2 other DDR gene mutations (10/64, 15.63%) also showed worse OS and RFS than patients with single mutation and wild type in DDR genes. (OS: 19 vs 35 months, P = 0.053; RFS: 3 vs 11 months, P = 0.084). Conclusions: Mutations in DDR signaling pathways predicted worse survival in TP53-mutated CRLM patients after surgery. These findings may be useful for clinical decision making in patients with tumor characteristics associated with poor prognosis and for risk stratification of patients in future clinical studies.

scholarly journals Pathogenetic and Prognostic Implications of Increased Mitochondrial Content in Multiple Myeloma

Cancers ◽  
2021 ◽  
Vol 13 (13) ◽  
pp. 3189
Author(s):  
Yanira Ruiz-Heredia ◽  
Alejandra Ortiz-Ruiz ◽  
Mehmet K. Samur ◽  
Vanesa Garrido ◽  
Laura Rufian ◽  
...  
Keyword(s):  
Mitochondrial Biogenesis ◽  
High Throughput Sequencing ◽  
Clinical Decision Making ◽  
Plasma Cells ◽  
Negative Impact ◽  
Progression Free Survival ◽  
Clinical Decision ◽  
Sequencing Analysis ◽  
Single Nucleotide Variants ◽  
Myeloma Cells

Many studies over the last 20 years have investigated the role of mitochondrial DNA (mtDNA) alterations in carcinogenesis. However, the status of the mtDNACN in MM and its implication in the pathogenesis of the disease remains unclear. We examined changes in plasma cell mtDNACN across different stages of MM by applying RT-PCR and high-throughput sequencing analysis. We observed a significant increase in the average mtDNACN in myeloma cells compared with healthy plasma cells (157 vs. 40 copies; p = 0.02). We also found an increase in mtDNACN in SMM and newly diagnosed MM (NDMM) paired samples and in consecutive relapses in the same patient. Survival analysis revealed the negative impact of a high mtDNACN in progression-free survival in NDMM (p = 0.005). Additionally, we confirmed the higher expression of mitochondrial biogenesis regulator genes in myeloma cells than in healthy plasma cells and we detected single nucleotide variants in several genes involved in mtDNA replication. Finally, we found that there was molecular similarity between “rapidly-progressing SMM” and MM regarding mtDNACN. Our data provide evidence that malignant transformation of myeloma cells involves the activation of mitochondrial biogenesis, resulting in increased mtDNA levels, and highlights vulnerabilities and potential therapeutic targets in the treatment of MM. Accordingly, mtDNACN tracking might guide clinical decision-making and management of complex entities such as high-risk SMM.

Preliminary Findings on the Use of Session Questionnaires to Improve Clinician-Client Alliance With Special Consideration to Clinical Education

2015 ◽  
Vol 25 (1) ◽  
pp. 50-60
Author(s):  
Anu Subramanian
Keyword(s):  
Graduate Students ◽  
Clinical Education ◽  
Clinical Decision Making ◽  
Rating Scale ◽  
Treatment Effectiveness ◽  
Clinical Decision ◽  
Added Value ◽  
Therapeutic Outcomes ◽  
Specific Feedback ◽  
Stakeholder Perspective

ASHA's focus on evidence-based practice (EBP) includes the family/stakeholder perspective as an important tenet in clinical decision making. The common factors model for treatment effectiveness postulates that clinician-client alliance positively impacts therapeutic outcomes and may be the most important factor for success. One strategy to improve alliance between a client and clinician is the use of outcome questionnaires. In the current study, eight parents of toddlers who attended therapy sessions at a university clinic responded to a session outcome questionnaire that included both rating scale and descriptive questions. Six graduate students completed a survey that included a question about the utility of the questionnaire. Results indicated that the descriptive questions added value and information compared to using only the rating scale. The students were varied in their responses regarding the effectiveness of the questionnaire to increase their comfort with parents. Information gathered from the questionnaire allowed for specific feedback to graduate students to change behaviors and created opportunities for general discussions regarding effective therapy techniques. In addition, the responses generated conversations between the client and clinician focused on clients' concerns. Involving the stakeholder in identifying both effective and ineffective aspects of therapy has advantages for clinical practice and education.

Clinical Decision-Making for Stroke and Aphasia in the Older Adult

2009 ◽  
Vol 14 (1) ◽  
pp. 4-11 ◽  
Author(s):  
Jacqueline Hinckley
Keyword(s):  
Executive Function ◽  
Cerebrovascular Disease ◽  
Cognitive Abilities ◽  
Clinical Decision Making ◽  
Clinical Decision ◽  
Cognitive Profile ◽  
Focal Lesion ◽  
Cognitive Profiles ◽  
Supportive Communication ◽  
Spaced Retrieval

Abstract A patient with aphasia that is uncomplicated by other cognitive abilities will usually show a primary impairment of language. The frequency of additional cognitive impairments associated with cerebrovascular disease, multiple (silent or diagnosed) infarcts, or dementia increases with age and can complicate a single focal lesion that produces aphasia. The typical cognitive profiles of vascular dementia or dementia due to cerebrovascular disease may differ from the cognitive profile of patients with Alzheimer's dementia. In order to complete effective treatment selection, clinicians must know the cognitive profile of the patient and choose treatments accordingly. When attention, memory, and executive function are relatively preserved, strategy-based and conversation-based interventions provide the best choices to target personally relevant communication abilities. Examples of treatments in this category include PACE and Response Elaboration Training. When patients with aphasia have co-occurring episodic memory or executive function impairments, treatments that rely less on these abilities should be selected. Examples of treatments that fit these selection criteria include spaced retrieval and errorless learning. Finally, training caregivers in the use of supportive communication strategies is helpful to patients with aphasia, with or without additional cognitive complications.

Debates in Dysphagia Management: How Do You Use Evidence-Based Practice in Your Dysphagia Patient Care?

2011 ◽  
Vol 20 (4) ◽  
pp. 121-123
Author(s):  
Jeri A. Logemann
Keyword(s):  
Decision Making ◽  
Patient Care ◽  
Clinical Outcomes ◽  
Clinical Judgment ◽  
Clinical Decision Making ◽  
Evidence Based Practice ◽  
Clinical Decision ◽  
Evidence Based ◽  
Clinical Method ◽  
Do So

Evidence-based practice requires astute clinicians to blend our best clinical judgment with the best available external evidence and the patient's own values and expectations. Sometimes, we value one more than another during clinical decision-making, though it is never wise to do so, and sometimes other factors that we are unaware of produce unanticipated clinical outcomes. Sometimes, we feel very strongly about one clinical method or another, and hopefully that belief is founded in evidence. Some beliefs, however, are not founded in evidence. The sound use of evidence is the best way to navigate the debates within our field of practice.

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