scholarly journals De novo individualized disease modules reveal the synthetic penetrance of genes and inform personalized treatment regimens

2021 ◽  
pp. gr.275889.121
Author(s):  
Taylor Weiskittel ◽  
Choong Yong Ung ◽  
Cristina Correia ◽  
Cheng Zhang ◽  
Hu Li
Keyword(s):  
Disease Gene ◽  
De Novo ◽  
Breast Cancers ◽  
Computational Pipeline ◽  
Disease Etiology ◽  
Treatment Regimens ◽  
Disease Module ◽  
Cancer Drivers ◽  
Individual Disease ◽  
Disease Modules

Current understandings of individual disease etiology and therapeutics are limited despite great need. To fill the gap, we propose a novel computational pipeline which collects potent disease gene cooperative pathways to envision individualized disease etiology and therapies. Our algorithm constructs individualized disease modules de novo which enable us to elucidate the importance of mutated genes in specific patients and to understand the synthetic penetrance of these genes across patients. We reveal that importance of notorious cancer drivers TP53 and PIK3CA fluctuate widely across breast cancers and peak in tumors with distinct numbers of mutations, and that rarely mutated genes such as XPO1 and PLEKHA1 have high disease module importance in specific individuals. Furthermore, individualized module disruption enables us to devise customized singular and combinatorial target therapies which were highly varied across patients demonstrating the need for precision therapeutics pipelines. As the first analysis of de novo individualized disease modules, we illustrate the power of individualized disease modules for precision medicine by providing deep novel insights on the activity of diseased genes in individuals.

scholarly journals What Is Known and Unknown About Twice-Weekly Hemodialysis

2015 ◽  
Vol 40 (4) ◽  
pp. 298-305 ◽  
Author(s):  
Yoshitsugu Obi ◽  
Rieko Eriguchi ◽  
Shuo-Ming Ou ◽  
Connie M. Rhee ◽  
Kamyar Kalantar-Zadeh
Keyword(s):  
Quality Of Life ◽  
De Novo ◽  
Urine Volume ◽  
Cost Effective ◽  
Standard Of Care ◽  
Treatment Regimens ◽  
Interdialytic Weight Gain ◽  
Cost Effective Treatment ◽  
Incremental Hemodialysis

Background: The 2006 Kidney Disease Outcomes Quality Initiative guidelines suggest twice-weekly or incremental hemodialysis for patients with substantial residual kidney function (RKF). However, in most affluent nations de novo and abrupt transition to thrice-weekly hemodialysis is routinely prescribed for all dialysis-naïve patients regardless of their RKF. We review historical developments in hemodialysis therapy initiation and revisit twice-weekly hemodialysis as an individualized, incremental treatment especially upon first transitioning to hemodialysis therapy. Summary: In the 1960's, hemodialysis treatment was first offered as a life-sustaining treatment in the form of long sessions (≥10 hours) administered every 5 to 7 days. Twice- and then thrice-weekly treatment regimens were subsequently developed to prevent uremic symptoms on a long-term basis. The thrice-weekly regimen has since become the ‘standard of care' despite a lack of comparative studies. Some clinical studies have shown benefits of high hemodialysis dose by more frequent or longer treatment times mainly among patients with limited or no RKF. Conversely, in selected patients with higher levels of RKF and particularly higher urine volume, incremental or twice-weekly hemodialysis may preserve RKF and vascular access longer without compromising clinical outcomes. Proposed criteria for twice-weekly hemodialysis include urine output >500 ml/day, limited interdialytic weight gain, smaller body size relative to RKF, and favorable nutritional status, quality of life, and comorbidity profile. Key Messages: Incremental hemodialysis including twice-weekly regimens may be safe and cost-effective treatment regimens that provide better quality of life for incident dialysis patients who have substantial RKF. These proposed criteria may guide incremental hemodialysis frequency and warrant future randomized controlled trials.

scholarly journals Spot 14: A Marker of Aggressive Breast Cancer and a Potential Therapeutic Target

Endocrinology ◽  
2006 ◽  
Vol 147 (9) ◽  
pp. 4048-4055 ◽  
Author(s):  
William B. Kinlaw ◽  
Jennifer L. Quinn ◽  
Wendy A. Wells ◽  
Christopher Roser-Jones ◽  
Joel T. Moncur
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Therapeutic Target ◽  
Milk Fat ◽  
Breast Cancer Cells ◽  
De Novo ◽  
Lipid Synthesis ◽  
Breast Cancers ◽  
Spot 14 ◽  
Aggressive Breast Cancer

Spot 14 (S14) is a nuclear protein that communicates the status of dietary fuels and fuel-related hormones to genes required for long-chain fatty acid synthesis. In mammary gland, S14 is important for both epithelial proliferation and milk fat production. The S14 gene is amplified in some breast cancers and is strongly expressed in most. High expression of S14 in primary invasive breast cancer is conspicuously predictive of recurrence. S14 mediates the induction of lipogenesis by progestin in breast cancer cells and accelerates their growth. Conversely, S14 knockdown impairs de novo lipid synthesis and causes apoptosis. We found that breast cancer cells do not express lipoprotein lipase (LPL) and hypothesize that they do not have access to circulating lipids unless the local environment supplies it. This may explain why primary breast cancers with low S14 do not survive transit from the LPL-rich mammary fat pad to areas devoid of LPL, such as lymph nodes, and thus do not appear as distant metastases. Thus, S14 is a marker for aggressive breast cancer and a potential target as well. Future effort will center on validation of S14 as a therapeutic target and producing antagonists of its action.

scholarly journals An Unusual Case of Infantile Spasms Due to a Pathogenic Variant in the MECP2 Gene

2019 ◽  
Vol 18 (01) ◽  
pp. 039-044
Author(s):  
Behshad Charkhand ◽  
Natarie Liu ◽  
Karlene T. Barrett ◽  
Walla Al-Hertani ◽  
Morris H. Scantlebury
Keyword(s):  
Unusual Case ◽  
De Novo ◽  
Epileptic Encephalopathy ◽  
Infantile Spasms ◽  
Mecp2 Gene ◽  
Disease Etiology ◽  
Epileptic Spasms ◽  
Uncertain Significance ◽  
Atypical Presentations ◽  
De Novo Variant

AbstractThe infantile spasms (IS) syndrome is a developmental epileptic encephalopathy disorder characterized by epileptic spasms occurring in infancy, hypsarrhythmia on the electroencephalography (EEG) and developmental arrest or regression. The etiologies include structural, metabolic, and genetic causes. We report an unusual case of IS due to a de novo variant in the MECP2 gene. The patient also had variants of uncertain significance in the SCN9A and SCN5A genes inherited from the father and mother, respectively. This report highlights the need for broad genetic testing in MECP2-related disorders with atypical presentations to better understand the disease etiology.

Contribution of de novo and mosaic TP53 mutations to Li-Fraumeni syndrome

2017 ◽  
Vol 55 (3) ◽  
pp. 173-180 ◽  
Author(s):  
Mariette Renaux-Petel ◽  
Françoise Charbonnier ◽  
Jean-Christophe Théry ◽  
Pierre Fermey ◽  
Gwendoline Lienard ◽  
...  
Keyword(s):  
Sanger Sequencing ◽  
De Novo ◽  
Multiple Primary Cancers ◽  
Breast Cancers ◽  
De Novo Mutations ◽  
Li Fraumeni Syndrome ◽  
Medical Laboratories ◽  
Li Fraumeni ◽  
Adrenocortical Carcinomas ◽  
Generation Sequencing

BackgroundDevelopment of tumours such as adrenocortical carcinomas (ACC), choroid plexus tumours (CPT) or female breast cancers before age 31 or multiple primary cancers belonging to the Li-Fraumeni (LFS) spectrum is, independently of the familial history, highly suggestive of a germline TP53 mutation. The aim of this study was to determine the contribution of de novo and mosaic mutations to LFS.Methods and resultsAmong 328 unrelated patients harbouring a germline TP53 mutation identified by Sanger sequencing and/or QMPSF, we could show that the mutations had occurred de novo in 40 cases, without detectable parental age effect. Sanger sequencing revealed two mosaic mutations in a child with ACC and in an unaffected father of a child with medulloblastoma. Re-analysis of blood DNA by next-generation sequencing, performed at a depth above 500X, from 108 patients suggestive of LFS without detectable TP53 mutations, allowed us to identify 6 additional cases of mosaic TP53 mutations, in 2/49 children with ACC, 2/21 children with CPT, in 1/31 women with breast cancer before age 31 and in a patient who developed an osteosarcoma at age 12, a breast carcinoma and a breast sarcoma at age 35.ConclusionsThis study performed on a large series of TP53 mutation carriers allows estimating the contribution to LFS of de novo mutations to at least 14% (48/336) and suggests that approximately one-fifth of these de novo mutations occur during embryonic development. Considering the medical impact of TP53 mutation identification, medical laboratories in charge of TP53 testing should ensure the detection of mosaic mutations.

Molecular characteristics and metastasis predictor genes of triple-negative breast cancer.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 1043-1043
Author(s):  
Wen-Hung Kuo ◽  
Yao-Yin Chang ◽  
Ming-Feng Hou ◽  
Eric Y Chuang ◽  
King-Jen Chang
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Early Stage ◽  
Gene Signature ◽  
Breast Cancers ◽  
Prognostic Signature ◽  
Characteristic Analysis ◽  
Disease Etiology ◽  
Breast Cancer Outcome

1043 Background: Triple-negative breast cancer(TNBC) is a subtype of breast cancer with aggressive tumor behavior and distinct disease etiology. Due to the lack of an effective targeted medicine, treatment options for triple-negative breast cancer are few and recurrence rates are high. Although various multi-gene prognostic markers have been proposed for the prediction of breast cancer outcome, most of them were proven clinically useful only for estrogen receptor-positive breast cancers. Reliable identification of triple-negative patients with a favorable prognosis is not yet possible. Methods: Clinicopathological information and microarray data from 157 invasive breast carcinomas were collected at National Taiwan University Hospital from 1995 to 2008. Gene expression data of 51 triple-negative and 106 luminal breast cancers were generated with oligonucleotide microarrays. A prognostic 45-gene signature for triple-negative breast cancer was identified using Student’s t test and receiver operating characteristic analysis. Results: Hierarchical clustering analysis revealed that the majority (94%) of triple-negative breast cancers were tightly clustered together carrying strong basal-like characteristics. A novel 45-gene signature giving 98% predictive accuracy in distant metastasis recurrence was identified in our triple-negative patient cohort. External validation of the prognostic signature in an independent microarray dataset of 59 early-stage triple-negative patients also obtained statistical significance (hazard ratio 2.29, 95% CI 1.04-5.06, Cox P = 0.04), outperforming five other published breast cancer prognostic signatures. The prognostic signature was statistically predictive with the node-negative triple-negative patients in the validation cohort. Conclusions: The 45-gene prognostic signature identified in this study revealed that TGF-β signaling in immune/inflammatory regulation may be critically involved in distant metastatic invasion of TNBC. The 45-gene signature, if further validated, may be a clinically useful tool in risk assessment of metastasis recurrence for early-stage triple-negative patients.

scholarly journals Gender, Race and Disease Etiology Predict De Novo Malignancy Risk After Liver Transplantation

2019 ◽  
Vol 103 (1) ◽  
pp. 91-100 ◽  
Author(s):  
Mamatha Bhat ◽  
Kristin Mara ◽  
Ross Dierkhising ◽  
Kymberly D. Watt
Keyword(s):  
Liver Transplantation ◽  
De Novo ◽  
Disease Etiology ◽  
Malignancy Risk ◽  
De Novo Malignancy

scholarly journals TRAIL-Induced Apoptosis in TRAIL-Resistant Breast Carcinoma Through Quercetin Cotreatment

2018 ◽  
Vol 12 ◽  
pp. 117822341774985 ◽  
Author(s):  
Jasmine M Manouchehri ◽  
Katherine A Turner ◽  
Michael Kalafatis
Keyword(s):  
Breast Cancer ◽  
Breast Carcinoma ◽  
Human Tumor ◽  
Breast Cancers ◽  
Treatment Regimens ◽  
Efficacious Treatment ◽  
Induced Apoptosis ◽  
Necrosis Factor ◽  
Mcf 7

Breast cancer is the most commonly diagnosed cancer in women. There is a continued interest for the development of more efficacious treatment regimens for breast carcinoma. Recombinant human tumor necrosis factor–related apoptosis-inducing ligand (rhTRAIL) shows potential as a potent anticancer therapeutic for the treatment of breast cancer, whereas displaying minimal toxicity to normal cells. However, the promise of rhTRAIL for the treatment of breast cancer is dismissed by the resistance to rhTRAIL-induced apoptosis exhibited by many breast cancers. Thus, a cotreatment strategy was examined by applying the natural compound quercetin (Q) as a sensitizing agent for rhTRAIL-resistant breast cancer BT-20 and MCF-7 cells. Quercetin was able to sensitize rhTRAIL-resistant breast cancers to rhTRAIL-induced apoptosis as detected by Western blotting through the proteasome-mediated degradation of c-FLIPL and through the upregulation of DR5 expression transcriptionally. Overall, these in vitro findings establish that Q is an effective sensitizing agent for rhTRAIL-resistant breast cancers.

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