Journal of Personalized Medicine

11 pages, 279 KiB

Open AccessArticle

A Data-Driven Approach to Carrier Screening for Common Recessive Diseases

by Anna V. Kiseleva, Marina V. Klimushina, Evgeniia A. Sotnikova, Mikhail G. Divashuk, Alexandra I. Ershova, Olga P. Skirko, Olga V. Kurilova, Anastasia A. Zharikova, Eleonora Yu. Khlebus, Irina A. Efimova, Maria S. Pokrovskaya, Petr A. Slominsky, Svetlana A. Shalnova, Alexey N. Meshkov and Oxana M. Drapkina

J. Pers. Med. 2020, 10(3), 140; https://doi.org/10.3390/jpm10030140 - 22 Sep 2020

Cited by 11 | Viewed by 3946

Abstract

Genetic screening is an advanced tool for reducing recessive disease burden. Nowadays, it is still unclear as to the number of genes or their variants that are necessary for effective screening. This paper describes the development of a carrier screening custom panel for [...] Read more.

Genetic screening is an advanced tool for reducing recessive disease burden. Nowadays, it is still unclear as to the number of genes or their variants that are necessary for effective screening. This paper describes the development of a carrier screening custom panel for cystic fibrosis, phenylketonuria, alpha-1 antitrypsin deficiency, and sensorineural hearing loss consisting of 116 variants in the CFTR, PAH, SERPINA1, and GJB2 genes. The approach is based on the cheapest and fastest method, on using a small number of genes, and on the estimation of the effectiveness of carriers’ detection. The custom panel was tested on a population-based cohort that included 1244 participants. Genotypes were determined by the TaqMan OpenArray Genotyping platform on the QuantStudio 12K Flex Real-Time PCR System. The frequency of heterozygotes in the Russian population was 16.87% or 1:6 (CI95%: 14.76–19.00% by Clopper-Pearson exact method): in CFTR—2.81% (1:36), PAH—2.33% (1:43), SERPINA1—4.90% (1:20), and GJB2—6.83% (1:15). The data on allele frequencies were obtained for the first time on a Russian population. The panel allows us to identify the vast majority of carriers of recessive diseases in the population. It is an effective approach to carrier screening for common recessive diseases. Full article

23 pages, 453 KiB

Open AccessArticle

Needs of Families with Children with Cerebral Palsy in Latvia and Factors Affecting These Needs

by Dace Bertule and Anita Vetra

J. Pers. Med. 2020, 10(3), 139; https://doi.org/10.3390/jpm10030139 - 22 Sep 2020

Cited by 2 | Viewed by 2938

Abstract

In order to provide targeted support to families who are raising children with developmental disorders, it is important to study the family needs and to understand circumstances that may affect them. The aim of this study was to identify the needs of the [...] Read more.

In order to provide targeted support to families who are raising children with developmental disorders, it is important to study the family needs and to understand circumstances that may affect them. The aim of this study was to identify the needs of the families with preschool children with cerebral palsy, and study how these needs relate to factors associated with families, children and rehabilitation services. Descriptive analysis showed that families living in Latvia most often need information, social and financial support and coordination of services, and they also need financial support to cover the costs of child care and treatment. The results of the data analysis support the hypothesis that factors characterising families, children with cerebral palsy and rehabilitation services affect the needs of the families with preschool children with cerebral palsy living in Latvia, and the unique impact of these factors depends on the type of needs. Regression analysis revealed that the most important factors affecting the needs of families were related with the socio-economic situation, as well as the support of peers and professionals. The availability and regularity of rehabilitation services, limitations to the child’s functions and health impairments were factors that affected family needs to a lesser extent. Full article

(This article belongs to the Special Issue Clinical Diagnosis and Personalized Treatment of Cerebral Palsy)

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12 pages, 267 KiB

Open AccessCommentary

Biomarkers for Alzheimer’s Disease (AD) and the Application of Precision Medicine

by Walter J. Lukiw, Andrea Vergallo, Simone Lista, Harald Hampel and Yuhai Zhao

J. Pers. Med. 2020, 10(3), 138; https://doi.org/10.3390/jpm10030138 - 21 Sep 2020

Cited by 21 | Viewed by 5349

Abstract

An accurate diagnosis of Alzheimer’s disease (AD) currently stands as one of the most difficult and challenging in all of clinical neurology. AD is typically diagnosed using an integrated knowledge and assessment of multiple biomarkers and interrelated factors. These include the patient’s age, [...] Read more.

An accurate diagnosis of Alzheimer’s disease (AD) currently stands as one of the most difficult and challenging in all of clinical neurology. AD is typically diagnosed using an integrated knowledge and assessment of multiple biomarkers and interrelated factors. These include the patient’s age, gender and lifestyle, medical and genetic history (both clinical- and family-derived), cognitive, physical, behavioral and geriatric assessment, laboratory examination of multiple AD patient biofluids, especially within the systemic circulation (blood serum) and cerebrospinal fluid (CSF), multiple neuroimaging-modalities of the brain’s limbic system and/or retina, followed up in many cases by post-mortem neuropathological examination to finally corroborate the diagnosis. More often than not, prospective AD cases are accompanied by other progressive, age-related dementing neuropathologies including, predominantly, a neurovascular and/or cardiovascular component, multiple-infarct dementia (MID), frontotemporal dementia (FTD) and/or strokes or ‘mini-strokes’ often integrated with other age-related neurological and non-neurological disorders including cardiovascular disease and cancer. Especially over the last 40 years, enormous research efforts have been undertaken to discover, characterize, and quantify more effectual and reliable biological markers for AD, especially during the pre-clinical or prodromal stages of AD so that pre-emptive therapeutic treatment strategies may be initiated. While a wealth of genetic, neurobiological, neurochemical, neuropathological, neuroimaging and other diagnostic information obtainable for a single AD patient can be immense: (i) it is currently challenging to integrate and formulate a definitive diagnosis for AD from this multifaceted and multidimensional information; and (ii) these data are unfortunately not directly comparable with the etiopathological patterns of other AD patients even when carefully matched for age, gender, familial genetics, and drug history. Four decades of AD research have repeatedly indicated that diagnostic profiles for AD are reflective of an extremely heterogeneous neurological disorder. This commentary will illuminate the heterogeneity of biomarkers for AD, comment on emerging investigative approaches and discuss why ‘precision medicine’ is emerging as our best paradigm yet for the most accurate and definitive prediction, diagnosis, and prognosis of this insidious and lethal brain disorder. Full article

(This article belongs to the Special Issue Novel Biomarkers in Alzheimer’s Disease)

21 pages, 3901 KiB

Open AccessArticle

Comprehensive Custom NGS Panel Validation for the Improvement of the Stratification of B-Acute Lymphoblastic Leukemia Patients

by Adrián Montaño, Jesús Hernández-Sánchez, Maribel Forero-Castro, María Matorra-Miguel, Eva Lumbreras, Cristina Miguel, Sandra Santos, Valentina Ramírez-Maldonado, José Luís Fuster, Natalia de Las Heras, Alfonso García-de Coca, Magdalena Sierra, Julio Dávila, Ignacio de la Fuente, Carmen Olivier, Juan Olazabal, Joaquín Martínez, Nerea Vega-García, Teresa González, Jesús María Hernández-Rivas and Rocío Benito Show full author list Hide full author list

J. Pers. Med. 2020, 10(3), 137; https://doi.org/10.3390/jpm10030137 - 21 Sep 2020

Cited by 5 | Viewed by 4967

Abstract

Background: B-acute lymphoblastic leukemia (B-ALL) is a hematological neoplasm of the stem lymphoid cell of the B lineage, characterized by the presence of genetic alterations closely related to the course of the disease. The number of alterations identified in these patients grows as [...] Read more.

Background: B-acute lymphoblastic leukemia (B-ALL) is a hematological neoplasm of the stem lymphoid cell of the B lineage, characterized by the presence of genetic alterations closely related to the course of the disease. The number of alterations identified in these patients grows as studies of the disease progress, but in clinical practice, the conventional techniques frequently used are only capable of detecting the most common alterations. However, techniques, such as next-generation sequencing (NGS), are being implemented to detect a wide spectrum of new alterations that also include point mutations. Methods: In this study, we designed and validated a comprehensive custom NGS panel to detect the main genetic alterations present in the disease in a single step. For this purpose, 75 B-ALL diagnosis samples from patients previously characterized by standard-of-care diagnostic techniques were sequenced. Results: The use of the custom NGS panel allowed the correct detection of the main genetic alterations present in B-ALL patients, including the presence of an aneuploid clone in 14 of the samples and some of the recurrent fusion genes in 35 of the samples. The panel was also able to successfully detect a number of secondary alterations, such as single nucleotide variants (SNVs) and copy number variations (CNVs) in 66 and 46 of the samples analyzed, respectively, allowing for further refinement of the stratification of patients. The custom NGS panel could also detect alterations with a high level of sensitivity and reproducibility when the findings obtained by NGS were compared with those obtained from other conventional techniques. Conclusions: The use of this custom NGS panel allows us to quickly and efficiently detect the main genetic alterations present in B-ALL patients in a single assay (SNVs and insertions/deletions (INDELs), recurrent fusion genes, CNVs, aneuploidies, and single nucleotide polymorphisms (SNPs) associated with pharmacogenetics). The application of this panel would thus allow us to speed up and simplify the molecular diagnosis of patients, helping patient stratification and management. Full article

(This article belongs to the Special Issue Personalized Medicine in Clinical Practice)

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11 pages, 2062 KiB

Open AccessArticle

Retrospective CT/MRI Texture Analysis of Rapidly Progressive Hepatocellular Carcinoma

by Charissa Kim, Natasha Cigarroa, Venkateswar Surabhi, Balaji Ganeshan and Anil K. Pillai

J. Pers. Med. 2020, 10(3), 136; https://doi.org/10.3390/jpm10030136 - 21 Sep 2020

Cited by 3 | Viewed by 3456

Abstract

Rapidly progressive hepatocellular carcinoma (RPHCC) is a subset of hepatocellular carcinoma that demonstrates accelerated growth, and the radiographic features of RPHCC versus non-RPHCC have not been determined. The purpose of this retrospective study was to use baseline radiologic features and texture analysis for [...] Read more.

Rapidly progressive hepatocellular carcinoma (RPHCC) is a subset of hepatocellular carcinoma that demonstrates accelerated growth, and the radiographic features of RPHCC versus non-RPHCC have not been determined. The purpose of this retrospective study was to use baseline radiologic features and texture analysis for the accurate detection of RPHCC and subsequent improvement of clinical outcomes. We conducted a qualitative visual analysis and texture analysis, which selectively extracted and enhanced imaging features of different sizes and intensity variation including mean gray-level intensity (mean), standard deviation (SD), entropy, mean of the positive pixels (MPP), skewness, and kurtosis at each spatial scaling factor (SSF) value of RPHCC and non-RPHCC tumors in a computed tomography (CT) cohort of n = 11 RPHCC and n = 11 non-RPHCC and a magnetic resonance imaging (MRI) cohort of n = 13 RPHCC and n = 10 non-RPHCC. There was a statistically significant difference across visual CT irregular margins p = 0.030 and CT texture features in SSF between RPHCC and non-RPHCC for SSF-6, coarse-texture scale, mean p = 0.023, SD p = 0.053, MPP p = 0.023. A composite score of mean SSF-6 binarized + SD SSF-6 binarized + MPP SSF-6 binarized + irregular margins was significantly different between RPHCC and non-RPHCC (p = 0.001). A composite score ≥3 identified RPHCC with a sensitivity of 81.8% and specificity of 81.8% (AUC = 0.884, p = 0.002). CT coarse-texture-scale features in combination with visually detected irregular margins were able to statistically differentiate between RPHCC and non-RPHCC. By developing an image-based, non-invasive diagnostic criterion, we created a composite score that can identify RPHCC patients at their early stages when they are still eligible for transplantation, improving the clinical course of patient care. Full article

(This article belongs to the Special Issue Biomedical Imaging and Cancers)

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25 pages, 3555 KiB

Open AccessArticle

Is Structured Exercise Performed with Supplemental Oxygen a Promising Method of Personalized Medicine in the Therapy of Chronic Diseases?

by Nils Freitag, Kenji Doma, Daniel Neunhaeuserer, Sulin Cheng, Wilhelm Bloch and Moritz Schumann

J. Pers. Med. 2020, 10(3), 135; https://doi.org/10.3390/jpm10030135 - 19 Sep 2020

Cited by 5 | Viewed by 5254

Abstract

Aim: This systematic review aimed to explore the literature to identify in which types of chronic diseases exercise with supplemental oxygen has previously been utilized and whether this type of personalized therapy leads to superior effects in physical fitness and well-being. Methods [...] Read more.

Aim: This systematic review aimed to explore the literature to identify in which types of chronic diseases exercise with supplemental oxygen has previously been utilized and whether this type of personalized therapy leads to superior effects in physical fitness and well-being. Methods: Databases (PubMed/MEDLINE, CINHAL, EMBASE, Web of knowledge and Cochrane Library) were searched in accordance with PRISMA. Eligibility criteria included adult patients diagnosed with any type of chronic diseases engaging in supervised exercise training with supplemental oxygen compared to normoxia. A random-effects model was used to pool effect sizes by standardized mean differences (SMD). Results: Out of the identified 4038 studies, 12 articles were eligible. Eleven studies were conducted in chronic obstructive pulmonary disease (COPD), while one study included coronary artery disease (CAD) patients. No statistical differences were observed for markers of physical fitness and patient-reported outcomes on well-being between the two training conditions (SMD −0.10; 95% CI −0.27, 0.08; p = 0.26). Conclusions: We found that chronic exercise with supplemental oxygen has mainly been utilized for COPD patients. Moreover, no superior long-term adaptations on physical fitness, functional capacity or patient-reported well-being were found, questioning the role of this method as a personalized medicine approach. Prospero registration: CRD42018104649. Full article

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12 pages, 217 KiB

Open AccessArticle

Genomics and Pharmacogenomics Knowledge, Attitude and Practice of Pharmacists Working in United Arab Emirates: Findings from Focus Group Discussions—A Qualitative Study

by Azhar T. Rahma, Iffat Elbarazi, Bassam R. Ali, George P. Patrinos, Luai A. Ahmed and Fatma Al Maskari

J. Pers. Med. 2020, 10(3), 134; https://doi.org/10.3390/jpm10030134 - 18 Sep 2020

Cited by 21 | Viewed by 3668

Abstract

(1) Background: Genomics and pharmacogenomics are relatively new fields in medicine in the United Arab Emirates (UAE). Understanding the knowledge, attitudes and current practices among pharmacists is an important pillar to establish the roadmap for implementing genomic medicine and pharmacogenomics; (2) Methods: A [...] Read more.

(1) Background: Genomics and pharmacogenomics are relatively new fields in medicine in the United Arab Emirates (UAE). Understanding the knowledge, attitudes and current practices among pharmacists is an important pillar to establish the roadmap for implementing genomic medicine and pharmacogenomics; (2) Methods: A qualitative method was used, with focus group discussions (FGDs) being conducted among pharmacists working in public and private hospitals in Abu Dhabi Emirate. Snowball sampling was used. Thematic inductive analysis was performed by two researchers independently. NVIVO software was used to establish the themes; (3) Results: Lack of knowledge of genomics and pharmacogenomics among pharmacists was one of the most prominent findings. Therefore, the role of pharmacist in making the right decisions was highlighted to be a barrier for pharmacogenomics implementation in the UAE. Pharmacists have a positive attitude toward pharmacogenomics, but they are preoccupied with concern of confidentiality. In addition, religion and culture shadowed their attitudes toward genetic testing; (4) Conclusions: It is highly recommended to introduce new courses and training workshops for healthcare providers to improve the opportunities for genomics and pharmacogenomics application in the UAE. Pharmacists agreed that the health authorities should take the lead for improving trust and confidence in the system for a better future in the era of genomics and pharmacogenomics. Full article

14 pages, 609 KiB

Open AccessArticle

An Exploratory Association Analysis of ABCB₁ rs1045642 and ABCB₁ rs4148738 with Non-Major Bleeding Risk in Atrial Fibrillation Patients Treated with Dabigatran or Apixaban

by Adela-Nicoleta Roşian, Mihaela Iancu, Adrian Pavel Trifa, Ştefan Horia Roşian, Cristina Mada, Cornelia Paula Gocan, Teodora Niţă, Sabina Istratoaie, Paul-Mihai Boarescu and Anca Dana Buzoianu

J. Pers. Med. 2020, 10(3), 133; https://doi.org/10.3390/jpm10030133 - 18 Sep 2020

Cited by 9 | Viewed by 3461

Abstract

(1) Background: The approach of bleeding complications in patients treated with non-vitamin K oral anticoagulants (NOACs) represents an important issue in clinical practice. Both dabigatran and apixaban are substrates for P-glycoprotein and, therefore, ABCB₁ gene variations may be useful in individualizing NOACs [...] Read more.

(1) Background: The approach of bleeding complications in patients treated with non-vitamin K oral anticoagulants (NOACs) represents an important issue in clinical practice. Both dabigatran and apixaban are substrates for P-glycoprotein and, therefore, ABCB₁ gene variations may be useful in individualizing NOACs treatment, especially in high-risk patients. (2) Methods: ABCB₁ rs1045642 and rs4148738 were determined in 218 atrial fibrillation patients treated with dabigatran or apixaban (70.94 ± 9.04 years; 51.83% men). (3) Results: Non-major bleeding appeared in 7.34% NOACs–treated patients. The logistic tested models based on the four genetic models revealed no significant association between the variant genotype of two ABCB₁ SNPs and the risk of bleeding (p > 0.05). Among the four two-locus haplotypes, TA and CA haplotypes had the highest frequency in NOACs-treated patients with bleeding, involving a possible positive association with the susceptibility of bleeding complications (OR = 1.04 and OR = 1.91, respectively). The logistic model found no significant association of estimated haplotypes with bleeding (p > 0.05) except for the TG haplotype which had a trend toward statistical significance (p = 0.092). Among the risk factors for bleeding, only age > 70 years and stroke/TIA showed a tendency toward statistical significance. (4) Conclusions: We found no significant associations between the studied ABCB₁ variant genotypes with non-major bleeding risk in NOACs-treated patients. A trend of association between TG haplotype with bleeding risk was observed, implying a protective role of this haplotype against bleeding in patients treated with dabigatran or apixaban. Full article

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14 pages, 1655 KiB

Open AccessArticle

Early Prediction of Tumor Response to Neoadjuvant Chemotherapy and Clinical Outcome in Breast Cancer Using a Novel FDG-PET Parameter for Cancer Stem Cell Metabolism

by Chanwoo Kim, Sang-Ah Han, Kyu Yeoun Won, Il Ki Hong and Deog Yoon Kim

J. Pers. Med. 2020, 10(3), 132; https://doi.org/10.3390/jpm10030132 - 17 Sep 2020

Cited by 8 | Viewed by 2820

Abstract

Cancer stem cells (CSCs) contribute to chemoresistance and tumor relapse. By using the distinct metabolic phenotype of CSC, we designed novel PET parameters for CSC metabolism and investigated their clinical values. Patients with breast cancer who underwent ¹⁸F-FDG PET/CT before neoadjuvant chemotherapy [...] Read more.

Cancer stem cells (CSCs) contribute to chemoresistance and tumor relapse. By using the distinct metabolic phenotype of CSC, we designed novel PET parameters for CSC metabolism and investigated their clinical values. Patients with breast cancer who underwent ¹⁸F-FDG PET/CT before neoadjuvant chemotherapy (NAC) were retrospectively included. We developed a method to measure CSC metabolism using standardized uptake value histogram data. The predictive value of novel CSC metabolic parameters for pathologic complete response (pCR) was assessed with multivariable logistic regression. The association between the CSC parameter and disease-free survival (DFS) was also determined. We identified 82 patients with HER2-positive/triple-negative subtypes and 38 patients with luminal tumors. After multivariable analysis, only metabolic tumor volume for CSC (MTVcsc) among metabolic parameters remained the independent predictor of pCR (OR, 0.12; p = 0.022). MTVcsc successfully predicted pathologic tumor response to NAC in HER2-positive/triple-negative subtypes (accuracy, 74%) but not in the luminal subtype (accuracy, 29%). MTVcsc was also predictive of DFS, with a 3-year DFS of 90% in the lower MTVcsc group (<1.75 cm³) versus 72% in the higher group (>1.75 cm³). A novel data-driven PET parameter for CSC metabolism provides early prediction of pCR after NAC and DFS in HER2-positive and triple-negative subtypes. Full article

(This article belongs to the Special Issue Biomedical Imaging and Cancers)

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21 pages, 5027 KiB

Open AccessArticle

Liquid lncRNA Biopsy for the Evaluation of Locally Advanced and Metastatic Squamous Cell Carcinomas of the Head and Neck

by Izabela Łasińska, Tomasz Kolenda, Kacper Guglas, Magda Kopczyńska, Joanna Sobocińska, Anna Teresiak, Norbert Oksza Strzelecki, Katarzyna Lamperska, Andrzej Mackiewicz and Jacek Mackiewicz

J. Pers. Med. 2020, 10(3), 131; https://doi.org/10.3390/jpm10030131 - 16 Sep 2020

Cited by 7 | Viewed by 2859

Abstract

Background: Long non-coding RNA (lncRNA) are RNA molecules that are more than 200 nucleotides long and have the ability to modify the activity of genes. They can be found in both healthy and cancer tissues, as well as in plasma, saliva and other [...] Read more.

Background: Long non-coding RNA (lncRNA) are RNA molecules that are more than 200 nucleotides long and have the ability to modify the activity of genes. They can be found in both healthy and cancer tissues, as well as in plasma, saliva and other bodily fluids. They can also be used as biomarkers of early detection, prognosis and chemotherapy resistance in several cancer types. Treatment of head and neck squamous cell carcinoma (HNSCC) patients with locally advanced disease is still difficult, and choice of treatment should be based on more precise and available biomarkers, such as those obtained from a liquid biopsy. For improvement of treatment efficacy, identification and clinical implementation of new biomarkers are of the utmost importance. Methods: Plasma samples drawn before (p1) and three cycles post (p2) (TPF: docetaxel, cisplatin, 5-fluorouracil/PF: cisplatin, 5-fluorouracil) chemotherapy from 53 HNSCC patients (17 with locally advanced and 36 with metastatic disease) and 14 healthy volunteers were studied. Expression levels of 90 lncRNA expression were analyzed using the qRT-PCR method, and the obtained results were compared between proper groups. Statistical analyses were carried out using Jupyter Notebooks (5.7.2), Python (ver. 3.6) and GraphPad Prism 8. Results: The study demonstrated the differences between the expressions of several lncRNA in cancer patients’ and healthy volunteers’ plasma, as well as between locally advanced and metastatic patients’ groups. A correlation between the response to systemic therapy and lncRNA expression levels was observed. Patients with a (high/low) expression of Alpha 250 and Emx2os showed statistically significant differences in progression free survival (PFS), as well as for overall survival (OS) depending on the level of Alpha 250, snaR, SNHG1. The univariate and multivariate Cox regression model showed Alpha 250 as the best prognostic factor for HNSCC patients. Conclusions: Liquid biopsies based on lncRNAs are promising diagnostic tools that can be used to differentiate between those with cancer and healthy individuals. Additionally, they can also serve as biomarkers for chemotherapy resistance. An identified, circulating lncRNA Alpha 250 seems to prove the best prognostic biomarker, associated with extended PFS and OS, and should be validated in a larger cohort in the future. Full article

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17 pages, 7771 KiB

Open AccessArticle

Bioinformatics Data Mining Repurposes the JAK2 (Janus Kinase 2) Inhibitor Fedratinib for Treating Pancreatic Ductal Adenocarcinoma by Reversing the KRAS (Kirsten Rat Sarcoma 2 Viral Oncogene Homolog)-Driven Gene Signature

by Li-Wei Liu, Yao-Yu Hsieh and Pei-Ming Yang

J. Pers. Med. 2020, 10(3), 130; https://doi.org/10.3390/jpm10030130 - 16 Sep 2020

Cited by 21 | Viewed by 4247

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is still one of the most aggressive and lethal cancer types due to the late diagnosis, high metastatic potential, and drug resistance. The development of novel therapeutic strategies is urgently needed. KRAS (Kirsten rat sarcoma 2 viral oncogene homolog) [...] Read more.

Pancreatic ductal adenocarcinoma (PDAC) is still one of the most aggressive and lethal cancer types due to the late diagnosis, high metastatic potential, and drug resistance. The development of novel therapeutic strategies is urgently needed. KRAS (Kirsten rat sarcoma 2 viral oncogene homolog) is the major driver mutation gene for PDAC tumorigenesis. In this study, we mined cancer genomics data and identified a common KRAS-driven gene signature in PDAC, which is related to cell–cell and cell–extracellular matrix (ECM) interactions. Higher expression of this gene signature was associated with poorer overall survival of PDAC patients. Connectivity Map (CMap) analysis and drug sensitivity profiling predicted that a clinically approved JAK2 (Janus kinase 2)-selective inhibitor, fedratinib (also known as TG-101348), could reverse the KRAS-driven gene signature and exhibit KRAS-dependent anticancer activity in PDAC cells. As an approved treatment for myelofibrosis, the pharmacological and toxicological profiles of fedratinib have been well characterized. It may be repurposed for treating KRAS-driven PDAC in the future. Full article

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3 pages, 171 KiB

Open AccessEditorial

Molecular Diagnosis and Novel Therapies for Neuromuscular Diseases

by Rika Maruyama and Toshifumi Yokota

J. Pers. Med. 2020, 10(3), 129; https://doi.org/10.3390/jpm10030129 - 16 Sep 2020

Cited by 3 | Viewed by 3600

Abstract

With the development of novel targeted therapies, including exon skipping/inclusion and gene replacement therapy, the field of neuromuscular diseases has drastically changed in the last several years. Until 2016, there had been no FDA-approved drugs to treat Duchenne muscular dystrophy (DMD), the most [...] Read more.

With the development of novel targeted therapies, including exon skipping/inclusion and gene replacement therapy, the field of neuromuscular diseases has drastically changed in the last several years. Until 2016, there had been no FDA-approved drugs to treat Duchenne muscular dystrophy (DMD), the most common muscular dystrophy. However, several new personalized therapies, including antisense oligonucleotides eteplirsen for DMD exon 51 skipping and golodirsen and viltolarsen for DMD exon 53 skipping, have been approved in the last 4 years. We are witnessing the start of a therapeutic revolution in neuromuscular diseases. However, the studies also made clear that these therapies are still far from a cure. Personalized genetic medicine for neuromuscular diseases faces several key challenges, including the difficulty of obtaining appropriate cell and animal models and limited its applicability. This Special Issue “Molecular Diagnosis and Novel Therapies for Neuromuscular/Musculoskeletal Diseases” highlights key areas of research progress that improve our understanding and the therapeutic outcomes of neuromuscular diseases in the personalized medicine era. Full article

(This article belongs to the Special Issue Molecular Diagnosis and Novel Therapies for Neuromuscular/Musculoskeletal Diseases)

13 pages, 1270 KiB

Open AccessArticle

XGBoost Improves Classification of MGMT Promoter Methylation Status in IDH1 Wildtype Glioblastoma

by Nguyen Quoc Khanh Le, Duyen Thi Do, Fang-Ying Chiu, Edward Kien Yee Yapp, Hui-Yuan Yeh and Cheng-Yu Chen

J. Pers. Med. 2020, 10(3), 128; https://doi.org/10.3390/jpm10030128 - 15 Sep 2020

Cited by 80 | Viewed by 7197

Abstract

Approximately 96% of patients with glioblastomas (GBM) have IDH1 wildtype GBMs, characterized by extremely poor prognosis, partly due to resistance to standard temozolomide treatment. O6-Methylguanine-DNA methyltransferase (MGMT) promoter methylation status is a crucial prognostic biomarker for alkylating chemotherapy resistance in patients with GBM. [...] Read more.

Approximately 96% of patients with glioblastomas (GBM) have IDH1 wildtype GBMs, characterized by extremely poor prognosis, partly due to resistance to standard temozolomide treatment. O6-Methylguanine-DNA methyltransferase (MGMT) promoter methylation status is a crucial prognostic biomarker for alkylating chemotherapy resistance in patients with GBM. However, MGMT methylation status identification methods, where the tumor tissue is often undersampled, are time consuming and expensive. Currently, presurgical noninvasive imaging methods are used to identify biomarkers to predict MGMT methylation status. We evaluated a novel radiomics-based eXtreme Gradient Boosting (XGBoost) model to identify MGMT promoter methylation status in patients with IDH1 wildtype GBM. This retrospective study enrolled 53 patients with pathologically proven GBM and tested MGMT methylation and IDH1 status. Radiomics features were extracted from multimodality MRI and tested by F-score analysis to identify important features to improve our model. We identified nine radiomics features that reached an area under the curve of 0.896, which outperformed other classifiers reported previously. These features could be important biomarkers for identifying MGMT methylation status in IDH1 wildtype GBM. The combination of radiomics feature extraction and F-core feature selection significantly improved the performance of the XGBoost model, which may have implications for patient stratification and therapeutic strategy in GBM. Full article

(This article belongs to the Special Issue Biomedical Imaging and Cancers)

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14 pages, 1179 KiB

Open AccessArticle

Radiomic Analysis of MRI Images is Instrumental to the Stratification of Ovarian Cysts

by Roxana-Adelina Lupean, Paul-Andrei Ștefan, Diana Sorina Feier, Csaba Csutak, Balaji Ganeshan, Andrei Lebovici, Bianca Petresc and Carmen Mihaela Mihu

J. Pers. Med. 2020, 10(3), 127; https://doi.org/10.3390/jpm10030127 - 14 Sep 2020

Cited by 11 | Viewed by 3575

Abstract

The imaging diagnosis of malignant ovarian cysts relies on their morphological features, which are not always specific to malignancy. The histological analysis of these cysts shows specific fluid characteristics, which cannot be assessed by conventional imaging techniques. This study investigates whether the texture-based [...] Read more.

The imaging diagnosis of malignant ovarian cysts relies on their morphological features, which are not always specific to malignancy. The histological analysis of these cysts shows specific fluid characteristics, which cannot be assessed by conventional imaging techniques. This study investigates whether the texture-based radiomics analysis (TA) of magnetic resonance (MRI) images of the fluid content within ovarian cysts can function as a noninvasive tool in differentiating between benign and malignant lesions. Twenty-eight patients with benign (n = 15) and malignant (n = 13) ovarian cysts who underwent MRI examinations were retrospectively included. TA of the fluid component was undertaken on an axial T2-weighted sequence. A comparison of resulted parameters between benign and malignant groups was undertaken using univariate, multivariate, multiple regression, and receiver operating characteristics analyses, with the calculation of the area under the curve (AUC). The standard deviation of pixel intensity was identified as an independent predictor of malignant cysts (AUC = 0.738; sensitivity, 61.54%; specificity, 86.67%). The prediction model was able to identify malignant lesions with 84.62% sensitivity and 80% specificity (AUC = 0.841). TA of the fluid contained within the ovarian cysts can differentiate between malignant and benign lesions and potentially act as a noninvasive tool augmenting the imaging diagnosis of ovarian cystic lesions. Full article

(This article belongs to the Special Issue Biomedical Imaging and Cancers)

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12 pages, 223 KiB

Open AccessArticle

Psychological and Medical Characteristics Associated with Non-Adherence to Prescribed Daily Inhaled Corticosteroid

by Brett G. Toelle, Guy B. Marks and Stewart M. Dunn

J. Pers. Med. 2020, 10(3), 126; https://doi.org/10.3390/jpm10030126 - 14 Sep 2020

Cited by 5 | Viewed by 2808

Abstract

Medication non-adherence is associated with sub-optimal asthma control. Identification of medical and psychological characteristics associated with non-adherence is important to enable a targeted and personalized approach when working with patients and for the development of interventions to improve patient outcomes by improving medication [...] Read more.

Medication non-adherence is associated with sub-optimal asthma control. Identification of medical and psychological characteristics associated with non-adherence is important to enable a targeted and personalized approach when working with patients and for the development of interventions to improve patient outcomes by improving medication adherence. We enrolled adults who had diagnosed asthma and who were prescribed daily inhaled corticosteroid medication. We used published and validated instruments to measure medical characteristics including asthma features, practical asthma knowledge and perceived involvement in care and psychological characteristics including anxiety, depression, optimism, and personality traits, to assess the relationship with medication non-adherence. A total of 126 participants provided data, with 64 (50.8%) of the participants identified as non-adherent. Multivariate analyses showed that younger age, high neuroticism scores and a previous asthma hospital admission were associated with non-adherence. Interestingly, depression was associated with a lower risk of non-adherence. This study showed that a personalized medicine approach would include interventions targeting those who are younger, who have been in hospital for asthma and who rate high on the neuroticism personality trait. Given the availability of effective medications for asthma, better understanding of the characteristics associated with non-adherence is important to enhance optimal self-management. Full article

12 pages, 1321 KiB

Open AccessArticle

The Cytokinesis-Block Micronucleus Assay on Human Isolated Fresh and Cryopreserved Peripheral Blood Mononuclear Cells

by Simon Sioen, Karlien Cloet, Anne Vral and Ans Baeyens

J. Pers. Med. 2020, 10(3), 125; https://doi.org/10.3390/jpm10030125 - 14 Sep 2020

Cited by 13 | Viewed by 4430

Abstract

The cytokinesis-block micronucleus (CBMN) assay is a standardized method used for genotoxicity studies. Conventional whole blood cultures (WBC) are often used for this assay, although the assay can also be performed on isolated peripheral blood mononuclear cell (PBMC) cultures. However, the standardization of [...] Read more.

The cytokinesis-block micronucleus (CBMN) assay is a standardized method used for genotoxicity studies. Conventional whole blood cultures (WBC) are often used for this assay, although the assay can also be performed on isolated peripheral blood mononuclear cell (PBMC) cultures. However, the standardization of a protocol for the PBMC CBMN assay has not been investigated extensively. The aim of this study was to optimize a reliable CBMN assay protocol for fresh and cryopreserved peripheral blood mononuclear cells (PBMCS), and to compare micronuclei (MNi) results between WBC and PBMC cultures. The G₀ CBMN assay was performed on whole blood, freshly isolated, and cryopreserved PBMCS from healthy human blood samples and five radiosensitive patient samples. Cells were exposed to 220 kV X-ray in vitro doses ranging from 0.5 to 2 Gy. The optimized PBMC CBMN assay showed adequate repeatability and small inter-individual variability. MNi values were significantly higher for WBC than for fresh PBMCS. Additionally, cryopreservation of PBMCS resulted in a significant increase of MNi values, while different cryopreservation times had no significant impact. In conclusion, our standardized CBMN assay on fresh and cryopreserved PBMCS can be used for genotoxicity studies, biological dosimetry, and radiosensitivity assessment. Full article

(This article belongs to the Special Issue Radiation Response Biomarkers for Individualised Cancer Treatments)

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13 pages, 2416 KiB

Open AccessArticle

Transcript Levels of Aldo-Keto Reductase Family 1 Subfamily C (AKR1C) Are Increased in Prostate Tissue of Patients with Type 2 Diabetes

by Andras Franko, Lucia Berti, Jörg Hennenlotter, Steffen Rausch, Marcus O. Scharpf, Martin Hrabĕ de Angelis, Arnulf Stenzl, Andreas L. Birkenfeld, Andreas Peter, Stefan Z. Lutz, Hans-Ulrich Häring and Martin Heni

J. Pers. Med. 2020, 10(3), 124; https://doi.org/10.3390/jpm10030124 - 12 Sep 2020

Cited by 8 | Viewed by 3418

Abstract

Aldo-keto reductase family 1 (AKR1) enzymes play a crucial role in diabetic complications. Since type 2 diabetes (T2D) is associated with cancer progression, we investigated the impact of diabetes on AKR1 gene expression in the context of prostate cancer (PCa) development. In this [...] Read more.

Aldo-keto reductase family 1 (AKR1) enzymes play a crucial role in diabetic complications. Since type 2 diabetes (T2D) is associated with cancer progression, we investigated the impact of diabetes on AKR1 gene expression in the context of prostate cancer (PCa) development. In this study, we analyzed benign (BEN) prostate and PCa tissue of patients with and without T2D. Furthermore, to replicate hyperglycemia in vitro, we treated the prostate adenocarcinoma cell line PC3 with increasing glucose concentrations. Gene expression was quantified using real-time qPCR. In the prostate tissue of patients with T2D, AKR1C1 and AKR1C2 transcripts were higher compared to samples of patients without diabetes. In PC3 cells, high glucose treatment induced the gene expression levels of AKR1C1, C2, and C3. Furthermore, both in human tissue and in PC3 cells, the transcript levels of AKR1C1, C2, and C3 showed positive associations with oncogenes, which are involved in proliferation processes and HIF1α and NFκB pathways. These results indicate that in the prostate glands of patients with T2D, hyperglycemia could play a pivotal role by inducing the expression of AKR1C1, C2, and C3. The higher transcript level of AKR1C was furthermore associated with upregulated HIF1α and NFκB pathways, which are major drivers of PCa carcinogenesis. Full article

(This article belongs to the Section Methodology, Drug and Device Discovery)

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16 pages, 314 KiB

Open AccessArticle

The Genomics and Metagenomics of Asthma Severity (GEMAS) Study: Rationale and Design

by Javier Perez-Garcia, José M. Hernández-Pérez, Ruperto González-Pérez, Olaia Sardón, Elena Martin-Gonzalez, Antonio Espuela-Ortiz, Elena Mederos-Luis, Ariel Callero, Esther Herrera-Luis, Paula Corcuera, Inmaculada Sánchez-Machín, Paloma Poza-Guedes, Luis Manuel González García, Purificación Ramírez-Martín, Lorenzo Pérez-Negrín, Hemily Izaguirre-Flores, Javier Barrios-Recio, Eva Pérez-Rodríguez, Julia Alcoba-Florez, José A. Cañas, José M. Rodrigo Muñoz, Victoria del Pozo, Javier Korta-Murua, Lina I. Pérez Méndez, Mariano Hernandez-Ferrer, Jesús Villar, Fabian Lorenzo-Diaz and Maria Pino-Yanes Show full author list Hide full author list

J. Pers. Med. 2020, 10(3), 123; https://doi.org/10.3390/jpm10030123 - 11 Sep 2020

Cited by 9 | Viewed by 4037

Abstract

Asthma exacerbations are a major contributor to the global disease burden, but no significant predictive biomarkers are known. The Genomics and Metagenomics of Asthma Severity (GEMAS) study aims to assess the role of genomics and the microbiome in severe asthma exacerbations. Here, we [...] Read more.

Asthma exacerbations are a major contributor to the global disease burden, but no significant predictive biomarkers are known. The Genomics and Metagenomics of Asthma Severity (GEMAS) study aims to assess the role of genomics and the microbiome in severe asthma exacerbations. Here, we present the design of GEMAS and the characteristics of patients recruited from March 2018 to March 2020. Different biological samples and demographic and clinical variables were collected from asthma patients recruited by allergy and pulmonary medicine units in several hospitals from Spain. Cases and controls were defined by the presence/absence of severe asthma exacerbations in the past year (oral corticosteroid use, emergency room visits, and/or asthma-related hospitalizations). A total of 137 cases and 120 controls were recruited. After stratifying by recruitment location (i.e., Canary Islands and Basque Country), cases and controls did not differ for most demographic and clinical variables (p > 0.05). However, cases showed a higher proportion of characteristics inherent to asthma exacerbations (impaired lung function, severe disease, uncontrolled asthma, gastroesophageal reflux, and use of asthma medications) compared to controls (p < 0.05). Similar results were found after stratification by recruitment unit. Thereby, asthma patients enrolled in GEMAS are balanced for potential confounders and have clinical characteristics that support the phenotype definition. GEMAS will improve the knowledge of potential biomarkers of asthma exacerbations. Full article

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15 pages, 1581 KiB

Open AccessArticle

Measuring IGF-1 and IGFBP-3 Profiles in Women Seeking Assisted Reproduction; Relationship to Clinical Parameters (Study 1)

by John L. Yovich, Syeda Zaidi, Minh D. K. Nguyen and Peter M. Hinchliffe

J. Pers. Med. 2020, 10(3), 122; https://doi.org/10.3390/jpm10030122 - 11 Sep 2020

Cited by 4 | Viewed by 3041

Abstract

This study examines the IGF serum profile (IGF-1, IGFBP-3 and the IGF Ratio) from 1633 women who undertook an Assessment Cycle prior to any treatment by assisted reproduction. The idea is to progressively study the IGF profile with a view to identify those [...] Read more.

This study examines the IGF serum profile (IGF-1, IGFBP-3 and the IGF Ratio) from 1633 women who undertook an Assessment Cycle prior to any treatment by assisted reproduction. The idea is to progressively study the IGF profile with a view to identify those women who may be classified as having adult growth hormone deficiency (AGHD) and who may benefit from specific dynamic endocrinological testing to identify a potential benefit from growth hormone adjuvant treatment. This first study evaluates the IGF profile on clinical parameters, namely age, body mass index (BMI) and stature. The study shows a significant linear reduction in IGF-1 levels across the four age groups (<35 years, 35–39 years, 40–44 years and ≥45 years; p < 0.001). However, there was no variation in IGFBP-3 levels but the IGF Ratio showed a progressive linear elevation with advancing age (p < 0.001). With respect to both BMI and stature, none of the IGF profile parameters showed any variation. We conclude that further studies are warranted to examine the notion of underlying AGHD in the causation of the well-known feature of age-related poor prognosis in assisted reproduction. Full article

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15 pages, 494 KiB

Open AccessArticle

Evaluating the Impact of Telehealth-Based, Diabetes Medication Training for Community Health Workers on Glycemic Control

by Casey N. Keegan, Craig A. Johnston, Victor J. Cardenas, Jr. and Elizabeth M. Vaughan

J. Pers. Med. 2020, 10(3), 121; https://doi.org/10.3390/jpm10030121 - 11 Sep 2020

Cited by 7 | Viewed by 3924

Abstract

Background: Diabetes is a major contributor to morbidity and mortality. Community Health Workers (CHWs) have been instrumental in improving patient outcomes. However, CHW training largely focuses on general diabetes concepts rather than medications. Providing accessible, diabetes medication training for CHWs has the potential [...] Read more.

Background: Diabetes is a major contributor to morbidity and mortality. Community Health Workers (CHWs) have been instrumental in improving patient outcomes. However, CHW training largely focuses on general diabetes concepts rather than medications. Providing accessible, diabetes medication training for CHWs has the potential to increase patient understanding, personalized care, and adherence, thereby improving outcomes. Objective: To evaluate the impact of a telehealth-based diabetes medication training for CHWs on patient outcomes as measured by HbA1c changes. Methods: We provided a 12-month weekly, telehealth (videoconference) medication training for CHWs who led 6-month diabetes programs for low-income Latino(a)s in community clinics. We measured participant HbA1c (primary outcome), blood pressure, and body mass index (BMI) changes. We evaluated CHW knowledge via two pre/post-tests: medication adverse events/side effects (TEST-1, months 1–6) and dosing, titration, and emergencies (TEST-2, months 7–12). We assessed CHW training application by their ability to identify patient, provider, and healthcare system medication barriers. Results: Participants’ (n = 55) HbA1c improved (9.0% (75 mmol/mol) to 7.8% (62 mmol/mol) (p = 0.001)). Blood pressure and BMI changes were not significant. CHWs improved their knowledge: TEST-1: 10.5-18.2/20.0 (p = 0.002), TEST-2: 10.3–17.3/19.0 (p = 0.0019). CHWs identified 984 patients (n = 610), providers (n = 151), and healthcare systems (n = 223) medication barriers during the 12-month training. Conclusions: Providing a telehealth-based, diabetes medication training program for CHWs allowed a personalized approach to identify barriers to care at several levels, which was associated with significant participant HbA1c reductions and improved CHW knowledge. This is a promising cost-effective, culturally sensitive strategy to improve diabetes care. Larger longitudinal evaluations are needed to fully understand the impact of CHW medication training. Full article

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14 pages, 1138 KiB

Open AccessReview

Minimal Residual Disease in Multiple Myeloma: State of the Art and Applications in Clinical Practice

by Alessandro Gozzetti, Donatella Raspadori, Francesca Bacchiarri, Anna Sicuranza, Paola Pacelli, Ilaria Ferrigno, Dania Tocci and Monica Bocchia

J. Pers. Med. 2020, 10(3), 120; https://doi.org/10.3390/jpm10030120 - 10 Sep 2020

Cited by 15 | Viewed by 4962

Abstract

Novel drugs have revolutionized multiple myeloma therapy in the last 20 years, with median survival that has doubled to up to 8–10 years. The introduction of therapeutic strategies, such as consolidation and maintenance after autologous stem cell transplants, has also ameliorated clinical results. [...] Read more.

Novel drugs have revolutionized multiple myeloma therapy in the last 20 years, with median survival that has doubled to up to 8–10 years. The introduction of therapeutic strategies, such as consolidation and maintenance after autologous stem cell transplants, has also ameliorated clinical results. The goal of modern therapies is becoming not only complete remission, but also the deepest possible remission. In this context, the evaluation of minimal residual disease by techniques such as next-generation sequencing (NGS) and next-generation flow (NGF) is becoming part of all new clinical trials that test drug efficacy. This review focuses on minimal residual disease approaches in clinical trials, with particular attention to real-world practices. Full article

(This article belongs to the Section Mechanisms of Diseases)

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25 pages, 1486 KiB

Open AccessReview

Application of Noninvasive Vagal Nerve Stimulation to Stress-Related Psychiatric Disorders

by James Douglas Bremner, Nil Z. Gurel, Matthew T. Wittbrodt, Mobashir H. Shandhi, Mark H. Rapaport, Jonathon A. Nye, Bradley D. Pearce, Viola Vaccarino, Amit J. Shah, Jeanie Park, Marom Bikson and Omer T. Inan

J. Pers. Med. 2020, 10(3), 119; https://doi.org/10.3390/jpm10030119 - 9 Sep 2020

Cited by 45 | Viewed by 14417

Abstract

Background: Vagal Nerve Stimulation (VNS) has been shown to be efficacious for the treatment of depression, but to date, VNS devices have required surgical implantation, which has limited widespread implementation. Methods: New noninvasive VNS (nVNS) devices have been developed which allow external stimulation [...] Read more.

Background: Vagal Nerve Stimulation (VNS) has been shown to be efficacious for the treatment of depression, but to date, VNS devices have required surgical implantation, which has limited widespread implementation. Methods: New noninvasive VNS (nVNS) devices have been developed which allow external stimulation of the vagus nerve, and their effects on physiology in patients with stress-related psychiatric disorders can be measured with brain imaging, blood biomarkers, and wearable sensing devices. Advantages in terms of cost and convenience may lead to more widespread implementation in psychiatry, as well as facilitate research of the physiology of the vagus nerve in humans. nVNS has effects on autonomic tone, cardiovascular function, inflammatory responses, and central brain areas involved in modulation of emotion, all of which make it particularly applicable to patients with stress-related psychiatric disorders, including posttraumatic stress disorder (PTSD) and depression, since dysregulation of these circuits and systems underlies the symptomatology of these disorders. Results: This paper reviewed the physiology of the vagus nerve and its relevance to modulating the stress response in the context of application of nVNS to stress-related psychiatric disorders. Conclusions: nVNS has a favorable effect on stress physiology that is measurable using brain imaging, blood biomarkers of inflammation, and wearable sensing devices, and shows promise in the prevention and treatment of stress-related psychiatric disorders. Full article

(This article belongs to the Special Issue Clinical Neurophysiology, Neuroimaging, and Neuromodulation of Neuropsychiatric Disorders)

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10 pages, 2120 KiB

Open AccessArticle

Personalized Tests in Paralympic Athletes: Aerobic and Anaerobic Performance Profile of Elite Wheelchair Rugby Players

by Giuseppe Marcolin, Nicola Petrone, Michael Benazzato, Francesco Bettella, Angela Gottardi, Luigi Salmaso, Livio Corain, Alfredo Musumeci, Stefano Masiero and Antonio Paoli

J. Pers. Med. 2020, 10(3), 118; https://doi.org/10.3390/jpm10030118 - 9 Sep 2020

Cited by 6 | Viewed by 3558

Abstract

In Paralympic sports, the goal of functional classifications is to minimize the impact of impairment on the outcome of the competition. The present cross-sectional study aimed to investigate aerobic and anaerobic personalized tests in Paralympic athletes and to correlate them with the classification [...] Read more.

In Paralympic sports, the goal of functional classifications is to minimize the impact of impairment on the outcome of the competition. The present cross-sectional study aimed to investigate aerobic and anaerobic personalized tests in Paralympic athletes and to correlate them with the classification of the international wheelchair rugby federation (IWRF). Sixteen elite players of the Italian wheelchair rugby team volunteered for the study. Aerobic (incremental test to exhaustion) and anaerobic (Wingate 30s all-out test, 5 and 10-meter sprint test, shuttle test, isometric test) sport-performance measurements were correlated singularly or grouped (Z scores) with the classification point. Moreover, a multivariate permutation-based ranking analysis investigated possible differences in the overall level of performance among the adjacent classified groups of players, considering the scores of each test. A statistically significant correlation between the performance parameters and the IWRF functional classification considering both aerobic and anaerobic personalized tests was detected (0.58 ≤ r ≤ 0.88; 0.0260 ≤ p ≤ 0.0001). The multivariate permutation-based ranking analysis showed differences only for the low-pointers versus mid-pointers (p = 0.0195) and high-pointers (p = 0.0075). Although single performance parameters correlated with athletes’ classification point, results of the multivariate permutation-based ranking analysis seem to suggest considering only the most significant anaerobic and sport-specific performance parameters among athletes. These should be combined with the physical assessment and the qualitative observation, which are already part of the classification process to improve its effectiveness. Full article

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14 pages, 244 KiB

Open AccessArticle

Influence of SH2B3, MTHFD1L, GGCX, and ITGB3 Gene Polymorphisms on theVariability on Warfarin Dosage Requirements and Susceptibility to CVD in the Jordanian Population

by Laith N. AL-Eitan, Ayah Y. Almasri, Rame H. Khasawneh and Mansour A. Alghamdi

J. Pers. Med. 2020, 10(3), 117; https://doi.org/10.3390/jpm10030117 - 9 Sep 2020

Cited by 5 | Viewed by 3428

Abstract

The purpose of this study was to investigate the effects of the SH2B3, MTHFD1L, GGCX, and ITGB3 gene variants on the efficacy of warfarin treatment and its effects on the risk of cardiovascular disorders in Jordanian patients. The selected genes [...] Read more.

The purpose of this study was to investigate the effects of the SH2B3, MTHFD1L, GGCX, and ITGB3 gene variants on the efficacy of warfarin treatment and its effects on the risk of cardiovascular disorders in Jordanian patients. The selected genes and their polymorphisms are involved in many Genome-Wide Association Study (GWAS) associated with cardiovascular disease and the variability of warfarin therapy. The current study conducted a genetic association and pharmacogenetics study in (212) Jordanian cardiovascular patients treated with warfarin and (213) healthy controls. DNA extraction and the Mass ARRAY™ system were used to genotype ten selected polymorphisms within four genes (SH2B3, MTHFD1L, GGCX, and ITGB3). This study confirmed a genetic association of MTHFD1L rs6922269 Single Nucleotide Polymorphism (SNP) with warfarin sensitivity during the initial and stabilization phases of treatment. Moreover, this SNP showed significant differences in the initial and maintenance doses of warfarin. This study also found an association between the genetic haplotypes (AGC and GAT) within the SH2B3 gene and responsiveness to warfarin. However, possession of an MTHFD1L rs491552 variant allele was found to affect the outcome measure of the international normalized ratio (INR) during the stabilization phase of warfarin treatment. In contrast, there was no association between all selected SNPs and susceptibility to cardiovascular disorders. This study extends the current understanding of the high variability of the warfarin response, including variability in dose requirements and susceptibility to cardiovascular disease in the Jordanian-Arab population. Other studies on a larger sample and in different ethnic groups could help to better understand the pharmacogenetics of warfarin and its application in personalized medicine. Full article

(This article belongs to the Special Issue Cardiovascular Disease Prevention in the Era of Personalized Medicine)

39 pages, 421 KiB

Open AccessReview

Significance of Blood and Cerebrospinal Fluid Biomarkers for Alzheimer’s Disease: Sensitivity, Specificity and Potential for Clinical Use

by Cristina d’Abramo, Luciano D’Adamio and Luca Giliberto

J. Pers. Med. 2020, 10(3), 116; https://doi.org/10.3390/jpm10030116 - 8 Sep 2020

Cited by 31 | Viewed by 8144

Abstract

Alzheimer’s disease (AD) is the most common type of dementia, affecting more than 5 million Americans, with steadily increasing mortality and incredible socio-economic burden. Not only have therapeutic efforts so far failed to reach significant efficacy, but the real pathogenesis of the disease [...] Read more.

Alzheimer’s disease (AD) is the most common type of dementia, affecting more than 5 million Americans, with steadily increasing mortality and incredible socio-economic burden. Not only have therapeutic efforts so far failed to reach significant efficacy, but the real pathogenesis of the disease is still obscure. The current theories are based on pathological findings of amyloid plaques and tau neurofibrillary tangles that accumulate in the brain parenchyma of affected patients. These findings have defined, together with the extensive neurodegeneration, the diagnostic criteria of the disease. The ability to detect changes in the levels of amyloid and tau in cerebrospinal fluid (CSF) first, and more recently in blood, has allowed us to use these biomarkers for the specific in-vivo diagnosis of AD in humans. Furthermore, other pathological elements of AD, such as the loss of neurons, inflammation and metabolic derangement, have translated to the definition of other CSF and blood biomarkers, which are not specific of the disease but, when combined with amyloid and tau, correlate with the progression from mild cognitive impairment to AD dementia, or identify patients who will develop AD pathology. In this review, we discuss the role of current and hypothetical biomarkers of Alzheimer’s disease, their specificity, and the caveats of current high-sensitivity platforms for their peripheral detection. Full article

(This article belongs to the Special Issue Novel Biomarkers in Alzheimer’s Disease)

36 pages, 4530 KiB

Open AccessReview

The Other Side of Alzheimer’s Disease: Influence of Metabolic Disorder Features for Novel Diagnostic Biomarkers

by Chiara Argentati, Ilaria Tortorella, Martina Bazzucchi, Carla Emiliani, Francesco Morena and Sabata Martino

J. Pers. Med. 2020, 10(3), 115; https://doi.org/10.3390/jpm10030115 - 6 Sep 2020

Cited by 8 | Viewed by 4906

Abstract

Nowadays, the amyloid cascade hypothesis is the dominant model to explain Alzheimer’s disease (AD) pathogenesis. By this hypothesis, the inherited genetic form of AD is discriminated from the sporadic form of AD (SAD) that accounts for 85–90% of total patients. The cause of [...] Read more.

Nowadays, the amyloid cascade hypothesis is the dominant model to explain Alzheimer’s disease (AD) pathogenesis. By this hypothesis, the inherited genetic form of AD is discriminated from the sporadic form of AD (SAD) that accounts for 85–90% of total patients. The cause of SAD is still unclear, but several studies have shed light on the involvement of environmental factors and multiple susceptibility genes, such as Apolipoprotein E and other genetic risk factors, which are key mediators in different metabolic pathways (e.g., glucose metabolism, lipid metabolism, energetic metabolism, and inflammation). Furthermore, growing clinical evidence in AD patients highlighted the presence of affected systemic organs and blood similarly to the brain. Collectively, these findings revise the canonical understating of AD pathogenesis and suggest that AD has metabolic disorder features. This review will focus on AD as a metabolic disorder and highlight the contribution of this novel understanding on the identification of new biomarkers for improving an early AD diagnosis. Full article

(This article belongs to the Special Issue Novel Biomarkers in Alzheimer’s Disease)

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27 pages, 1042 KiB

Open AccessReview

Biomarkers for Alzheimer’s Disease Early Diagnosis

by Eva Ausó, Violeta Gómez-Vicente and Gema Esquiva

J. Pers. Med. 2020, 10(3), 114; https://doi.org/10.3390/jpm10030114 - 4 Sep 2020

Cited by 76 | Viewed by 15292

Abstract

Alzheimer’s disease (AD) is the most common cause of dementia, affecting the central nervous system (CNS) through the accumulation of intraneuronal neurofibrillary tau tangles (NFTs) and β-amyloid plaques. By the time AD is clinically diagnosed, neuronal loss has already occurred in many brain [...] Read more.

Alzheimer’s disease (AD) is the most common cause of dementia, affecting the central nervous system (CNS) through the accumulation of intraneuronal neurofibrillary tau tangles (NFTs) and β-amyloid plaques. By the time AD is clinically diagnosed, neuronal loss has already occurred in many brain and retinal regions. Therefore, the availability of early and reliable diagnosis markers of the disease would allow its detection and taking preventive measures to avoid neuronal loss. Current diagnostic tools in the brain, such as magnetic resonance imaging (MRI), positron emission tomography (PET) imaging, and cerebrospinal fluid (CSF) biomarkers (Aβ and tau) detection are invasive and expensive. Brain-secreted extracellular vesicles (BEVs) isolated from peripheral blood have emerged as novel strategies in the study of AD, with enormous potential as a diagnostic evaluation of therapeutics and treatment tools. In addition; similar mechanisms of neurodegeneration have been demonstrated in the brain and the eyes of AD patients. Since the eyes are more accessible than the brain, several eye tests that detect cellular and vascular changes in the retina have also been proposed as potential screening biomarkers. The aim of this study is to summarize and discuss several potential markers in the brain, eye, blood, and other accessible biofluids like saliva and urine, and correlate them with earlier diagnosis and prognosis to identify individuals with mild symptoms prior to dementia. Full article

(This article belongs to the Special Issue Novel Biomarkers in Alzheimer’s Disease)

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24 pages, 1560 KiB

Open AccessReview

A Genotyping/Phenotyping Approach with Careful Clinical Monitoring to Manage the Fluoropyrimidines-Based Therapy: Clinical Cases and Systematic Review of the Literature

by Valeria Conti, Emanuela De Bellis, Valentina Manzo, Francesco Sabbatino, Francesco Iannello, Fabrizio Dal Piaz, Viviana Izzo, Bruno Charlier, Berenice Stefanelli, Martina Torsiello, Teresa Iannaccone, Albino Coglianese, Francesca Colucci, Stefano Pepe and Amelia Filippelli

J. Pers. Med. 2020, 10(3), 113; https://doi.org/10.3390/jpm10030113 - 3 Sep 2020

Cited by 8 | Viewed by 4331

Abstract

Fluoropyrimidines (FP) are mainly metabolised by dihydropyrimidine dehydrogenase (DPD), encoded by the DPYD gene. FP pharmacogenetics, including four DPYD polymorphisms (DPYD-PGx), is recommended to tailor the FP-based chemotherapy. These polymorphisms increase the risk of severe toxicity; thus, the DPYD-PGx should [...] Read more.

Fluoropyrimidines (FP) are mainly metabolised by dihydropyrimidine dehydrogenase (DPD), encoded by the DPYD gene. FP pharmacogenetics, including four DPYD polymorphisms (DPYD-PGx), is recommended to tailor the FP-based chemotherapy. These polymorphisms increase the risk of severe toxicity; thus, the DPYD-PGx should be performed prior to starting FP. Other factors influence FP safety, therefore phenotyping methods, such as the measurement of 5-fluorouracil (5-FU) clearance and DPD activity, could complement the DPYD-PGx. We describe a case series of patients in whom we performed DPYD-PGx (by real-time PCR), 5-FU clearance and a dihydrouracil/uracil ratio (as the phenotyping analysis) and a continuous clinical monitoring. Patients who had already experienced severe toxicity were then identified as carriers of DPYD variants. The plasmatic dihydrouracil/uracil ratio (by high-performance liquid chromatography (HPLC)) ranged between 1.77 and 7.38. 5-FU clearance (by ultra-HPLC with tandem mass spectrometry) was measured in 3/11 patients. In one of them, it reduced after the 5-FU dosage was halved; in the other case, it remained high despite a drastic dosage reduction. Moreover, we performed a systematic review on genotyping/phenotyping combinations used as predictive factors of FP safety. Measuring the plasmatic 5-FU clearance and/or dihydrouracil/uracil (UH2/U) ratio could improve the predictive potential of DPYD-PGx. The upfront DPYD-PGx combined with clinical monitoring and feasible phenotyping method is essential to optimising FP-based chemotherapy. Full article

(This article belongs to the Special Issue Pharmacogenomics of Oncology Therapies)

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16 pages, 2483 KiB

Open AccessArticle

Immunohistochemical Characterization of Immune Infiltrate in Tumor Microenvironment of Glioblastoma

by Hassan Rahimi Koshkaki, Simone Minasi, Alessio Ugolini, Gianluca Trevisi, Chiara Napoletano, Ilaria G. Zizzari, Marco Gessi, Felice Giangaspero, Annunziato Mangiola, Marianna Nuti, Francesca R. Buttarelli and Aurelia Rughetti

J. Pers. Med. 2020, 10(3), 112; https://doi.org/10.3390/jpm10030112 - 3 Sep 2020

Cited by 23 | Viewed by 4874

Abstract

Background: Glioblastoma (GBM) is the most common primary malignant brain cancer in adults, with very limited therapeutic options. It is characterized by a severe immunosuppressive milieu mostly triggered by suppressive CD163⁺ tumor-associated macrophages (TAMs). The efficacy of immune checkpoint inhibitor interventions aimed [...] Read more.

Background: Glioblastoma (GBM) is the most common primary malignant brain cancer in adults, with very limited therapeutic options. It is characterized by a severe immunosuppressive milieu mostly triggered by suppressive CD163⁺ tumor-associated macrophages (TAMs). The efficacy of immune checkpoint inhibitor interventions aimed at rescuing anti-tumor immunity has not been proved to date. Thus, it is critically important to investigate the immunomodulatory mechanisms acting within the GBM microenvironment for the better design of immunotherapeutic strategies. Methods: The immunohistochemical analysis of a panel of immune biomarkers (CD3, FoxP3, CD163, IDO, PDL-1, PD-1 and TIGIT) was performed in paired samples of the tumor core (TC) and peritumoral area (PTA) of nine GBM patients. Results: CD163⁺ cells were the most common cell type in both the PTA and TC. IDO and PDL-1 were expressed in most of the TC samples, frequently accompanied by TIGIT expression; on the contrary, they were almost absent in the PTA. CD3⁺ cells were present in both the TC and PTA, to a lesser extent than CD163⁺ cells; they often were accompanied by PD-1 expression, especially in the TC. FoxP3 was scarcely present. Conclusion: Distinct inhibitory mechanisms can act simultaneously in both the TC and PTA to contribute to the strong immunosuppression observed within the GBM microenvironment. Nevertheless, the PTA shows strongly reduced immunosuppression when compared to the TC, thus representing a potential target for immunotherapies. Moreover, our results support the working hypothesis that immunosuppression and T-cell exhaustion can be simultaneously targeted to rescue anti-tumor immunity in GBM patients. Full article

(This article belongs to the Special Issue Immunocyto/Histochemistry in the Era of Immunotherapy)

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11 pages, 243 KiB

Open AccessFeature PaperReview

Advances in Genetic Characterization and Genotype–Phenotype Correlation of Duchenne and Becker Muscular Dystrophy in the Personalized Medicine Era

by Omar Sheikh and Toshifumi Yokota

J. Pers. Med. 2020, 10(3), 111; https://doi.org/10.3390/jpm10030111 - 3 Sep 2020

Cited by 19 | Viewed by 6030

Abstract

Currently, Duchenne muscular dystrophy (DMD) and the related condition Becker muscular dystrophy (BMD) can be usually diagnosed using physical examination and genetic testing. While BMD features partially functional dystrophin protein due to in-frame mutations, DMD largely features no dystrophin production because of out-of-frame [...] Read more.

Currently, Duchenne muscular dystrophy (DMD) and the related condition Becker muscular dystrophy (BMD) can be usually diagnosed using physical examination and genetic testing. While BMD features partially functional dystrophin protein due to in-frame mutations, DMD largely features no dystrophin production because of out-of-frame mutations. However, BMD can feature a range of phenotypes from mild to borderline DMD, indicating a complex genotype–phenotype relationship. Despite two mutational hot spots in dystrophin, mutations can arise across the gene. The use of multiplex ligation amplification (MLPA) can easily assess the copy number of all exons, while next-generation sequencing (NGS) can uncover novel or confirm hard-to-detect mutations. Exon-skipping therapy, which targets specific regions of the dystrophin gene based on a patient’s mutation, is an especially prominent example of personalized medicine for DMD. To maximize the benefit of exon-skipping therapies, accurate genetic diagnosis and characterization including genotype–phenotype correlation studies are becoming increasingly important. In this article, we present the recent progress in the collection of mutational data and optimization of exon-skipping therapy for DMD/BMD. Full article

(This article belongs to the Special Issue Understanding Neuromuscular Health and Disease: Advances in Genetics, Omics, and Molecular Function)

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J. Pers. Med., Volume 10, Issue 3 (September 2020) – 86 articles

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