Miracle-dz/UniFAR-FTUs huggingface dataset:
P21/ WAF1 and cyclin D1 variants and oral squamous cell carcinoma.

BACKGROUND Genetic factors are known to be involved in oral squamous cell carcinoma (OSCC) development. METHOD We evaluated a possible association between CCND1 A870G and P21/WAF1 C98A polymorphisms and OSCC, as well as the impact of the genotypes on protein immunoexpression. The study group consisted of 80 individuals with histopathological diagnosis of OSCC and the control group consisted of 80 healthy individuals without oral lesions and matched by age, sex and tobacco usage. The genotypes were studied by the polymerase chain reaction and restriction fragment length polymorphic analysis. Paraffin-embedded sections were used for immunohistochemical analysis. RESULTS No statistical association between CCND1 and/or P21/WAF1 genotypes and OSCC was demonstrated, although we found that people harbouring the combined presence of at least one variant allele of both genes showed a 1.8 times more chance of developing OSCC compared to the referent genotype. OSCC tumours from individuals with P21 heterozygous genotype showed a significantly higher immunopositivity than tumours from wild-type individuals. CONCLUSION The present study did not demonstrate a significant association between CCND1 and / or P21 / WAF1 genotypes and OSCC. However, P21 protein expression in OSCC tumours is affected by P21 / WAF1 genotype.
Human genetic insights into lipoproteins and risk of cardiometabolic disease

Purpose of review Human genetic studies have been successfully used to identify genes and pathways relevant to human biology. Using genetic instruments composed of loci associated with human lipid traits, recent studies have begun to clarify the causal role of major lipid fractions in risk of cardiometabolic disease. Recent findings The causal relationship between LDL cholesterol and coronary disease has been firmly established. Of the remaining two major fractions, recent studies have found that HDL cholesterol is not likely to be a causal particle in atherogenesis, and have instead shifted the causal focus to triglyceride-rich lipoproteins. Subsequent results are refining this view to suggest that triglycerides themselves might not be causal, but instead may be a surrogate for the causal cholesterol content within this fraction. Other studies have used a similar approach to address the association between lipid fractions and risk of type 2 diabetes. Beyond genetic variation in the target of statin medications, reduced LDL cholesterol associated with multiple genes encoding current or prospective drug targets associated with increased diabetic risk. In addition, genetically lower HDL cholesterol and genetically lower triglycerides both appear to increase risk of type 2 diabetes. Summary Results of these and future human genetic studies are positioned to provide substantive insights into the causal relationship between lipids and human disease, and should highlight mechanisms with important implications for our understanding of human biology and future lipid-altering therapeutic development.
Lumbar Interbody Fusion: Current Status

Lumbar interbody fusion techniques have been used for various indications since originally described 50 years ago. Technologic advances and improvements in our understanding of biomechanical principles have led to a refinement of the indications for and techniques used for the performance of lumbar interbody fusion. Minimally incisional techniques, the use of bone graft substitutes and extenders, and computerized navigation strategies have contributed to decreasing morbidity and generally improving outcomes. The purpose of this review is to describe the current “state of the art” of lumbar interbody fusion and to comment upon the current and future role of lumbar interbody fusion techniques in the management of lumbar spine disorders.
Punch graft versus follicular hair transplantation in the treatment of stable vitiligo

ABSTRACT Objective: To compare the efficacy of follicular hair transplantation and mini punch graft in the treatment of stable vitiligo. Methods: Thirty-two patients with stable vitiligo were included in this comparative study. A single patch from each patient was divided into two halves: one half was treated by punch graft, while the other half was treated by follicular hair transplantation followed by excimer light twice weekly, and the outcome was assessed at 0, 1, 3 and 6 months post operatively by photography and quartile scale. Results: At the final visit, the percentage of improvement of vitiligo in punch graft-treated side was significantly higher than that in follicular hair transplantation-treated side (p < 0.05). Also, repigmentation after punch grafting occurred after a mean period of 2.5 ± 0.5 weeks (range, 2–3 weeks), while after follicular hair transplantation, repigmentation occurred after 5.2 ± 1.9 weeks (range, 5–8 weeks) (p < 0.05). Cobblestone appearance was the most common complication after punch graft; it occurred in 29 patients (90%), while no reported side effects occurred after follicular graft technique. Conclusion: Punch grafting is more effective than follicular grafting in the treatment of stable vitiligo; however, follicular hair transplantation is cosmetically better, so we recommend it in exposed areas as face.
Somatic mutations in the notch, NF‐KB, PIK3CA, and hedgehog pathways in human breast cancers

Exome sequencing of human breast cancers has revealed a substantial number of candidate cancer genes with recurring but infrequent somatic mutations. To determine more accurately their mutation prevalence, we performed a mutation analysis of 36 novel candidate cancer genes in 96 human breast cancers. Somatic mutations with potential impact on protein function were observed in the genes ADAM12, CENTB1, CENTG1, DIP2C, GLI1, GRIN2D, HDLBP, IKBKB, KPNA5, NFKB1, NOTCH1, and OTOF. These findings strengthen the evidence for involvement of the Notch, Hedgehog, NF‐KB, and PIK3CA pathways in breast cancer development, and point to novel processes that likely are involved. © 2012 Wiley Periodicals, Inc.
FAS and ErbB2 expression in early local recurrent oral cancer.

BACKGROUND Local failure occurs in 13.9-62.6% and it is a well known indicator of poor prognosis in patients with oral squamous cell carcinoma (OSCC), despite aggressive treatments. The purpose of this study was to investigate the value of histopathology and molecular biomarkers in predicting the development of early local recurrence. METHODS This study included a total of 69 patients. There were 23 patients with early recurrent OSCC and 46 patients without local recurrence with the same clinical stage and tumor site, in a pair-matched study design. Their charts were retrospectively analyzed. All surgical specimens of the primary tumors were evaluated according to the system proposed by Anneroth et al. and immunohistochemical for ErbB2 and FAS were performed. RESULTS A significant correlation of early local recurrence with grade of histological malignancy (more than 15 points) was observed (Fisher's exact test, P = 0.03). Early local recurrence was also significantly associated with weak FAS expression and strong intracytoplasmic ErbB2 staining (Mantel-Haenszal chi-square, P = 0.0038 and P = 0.0068, respectively). Histological grade of malignancy (more than 15 points) was also correlated with reduced survival (log-rank, P = 0.06). Among the histopathological parameters, keratinization, pattern of invasion and inflammation were important for overall survival (log-rank, P < 0.0001). Regarding the biomarkers, only FAS was significantly associated with overall survival (log-rank, P = 0.0002). Moreover, a positive correlation of FAS and membrane ErbB2 expression with keratinization was noticed. CONCLUSION Histopathological characteristics and the expression of FAS and ErbB2 carry prognosis importance in local recurrence and overall survival in OSCC.
Cell‐free microRNAs as diagnostic, prognostic, and predictive biomarkers for lung cancer

Lung cancer is the most common cancer worldwide, accounting for over 1.37 million deaths annually. The clinical outcome and management of lung cancer patients could be substantially improved by the implementation of non‐invasive biomarker assays for the early detection, prognosis as well as prediction and monitoring of treatment response. MicroRNAs (miRNAs) have been implicated in the regulation of virtually all signaling circuits within a cell and their dysregulation has been shown to play an essential role in the development and progression of cancer. Recently, miRNAs were found to be released into the circulation and to exist there in a remarkably stable form. Furthermore, various cancers were shown to leave specific miRNA fingerprints in the blood of patients suggesting that cell‐free miRNAs could serve as non‐invasive biomarkers for the detection or monitoring of cancer and putative therapeutic targets. Since that, a considerable effort has been devoted to decode the information carried by circulating miRNAs. In the current review, we give an insight into the mechanisms of miRNA release into the bloodstream, their putative functional significance and systematically review the studies focused on the identification of cell‐free miRNAs with the diagnostic, prognostic, and predictive significance in lung cancer and discuss their potential clinical utility. © 2012 Wiley Periodicals, Inc.
Acute Respiratory Distress Syndrome: Potential Therapeutic Interventions

From the perspective of pathophysiology, the acute respiratory distress syndrome (ARDS) is probably one of the two or three most studied acute processes occurring in the medical intensive care unit. Most of what is known about this severe clinical illness and the mediators associated with it has come from the study of relevant animal models. In the mid1970s, the development of the sheep model of ARDS and, later, the porcine model led to the discovery of a wide variety of lipid mediators, amines, cytokines, proteases, etc. Documentation of the presence of highly toxic mediators associated with the development of ARDS has led to a flurry of activity in drug development in this area. There is now a steady flow of new ideas and compounds—and newly discovered potential mediators—so that the odds of finding an effective treatment have substantially increased.
Nanoscale Deformation and Nanomechanical Properties of Soft Matter Study Cases: Polydimethylsiloxane, Cells and Tissues

Nanoindentation technique was used to investigate the nanomechanical behaviour of different soft materials. Polydimethylsiloxane (PDMS), cells and tissues were examined. The nanomechanical properties (with loading rate and creep study), namely, the hardness (𝐻) and the elastic modulus (𝐸) of PDMS, were determined. A classical Hertzian contact analysis was also performed in order to obtain values of 𝐸. Moreover, the plastic deformation where no load had yet been applied to PDMS was investigated (zero load plastic deformation). Finally, the difficulties of measuring the nanomechanical properties (𝐻&𝐸) of cells and tissues were evaluated, showing the need for a modification of the current experimental protocols for preparing and mechanically testing in a mode that maintains their structure and their biological functioning in order to make indentation results more reproducible. Additionally, finite element method is used in order to simulate the nanoindentation of PDMS in correlation with experimental data.
Cytogenetic alterations and their molecular genetic correlates in head and neck squamous cell carcinoma: A next generation window to the biology of disease

Cytogenetic alterations underlie the development of head and neck squamous cell carcinoma (HNSCC), whether tobacco and alcohol use, betel nut chewing, snuff or human papillomavirus (HPV) causes the disease. Many of the molecular genetic aberrations in HNSCC result from these cytogenetic alterations. This review presents a brief introduction to the epidemiology of HNSCC, and discusses the role of HPV in the disease, cytogenetic alterations and their frequencies in HNSCC, their molecular genetic and The Cancer Genome Atlas (TCGA) correlates, prognostic implications, and possible therapeutic considerations. The most frequent cytogenetic alterations in HNSCC are gains of 5p14‐15, 8q11‐12, and 20q12‐13, gains or amplifications of 3q26, 7p11, 8q24, and 11q13, and losses of 3p, 4q35, 5q12, 8p23, 9p21‐24, 11q14‐23, 13q12‐14, 18q23, and 21q22. To understand their effects on tumor cell biology and response to therapy, the cytogenetic findings in HNSCC are increasingly being examined in the context of the biochemical pathways they disrupt. The goal is to minimize morbidity and mortality from HNSCC using cytogenetic abnormalities to identify valuable diagnostic biomarkers for HNSCC, prognostic biomarkers of tumor behavior, recurrence risk, and outcome, and predictive biomarkers of therapeutic response to identify the most efficacious treatment for each individual patient's tumor, all based on a detailed understanding of the next generation biology of HNSCC. © 2014 Wiley Periodicals, Inc.
Glycemic memory

Purpose of review The mistake of predicting the future is perhaps not tending to repressed or past memories. Hamlet's 17th-Century soliloquy ‘the heartache and the thousand natural shocks, that flesh is heir to’, (3.1. 7–8) is a tale that looks beyond the present by linking the past with the future. The present article examines the resurgence in the field to understand gene-regulating epigenetic changes conferring glycemic memory. Recent findings Chromatin modifications are critical in regulating genome structure and function and despite the significant advances of recent years in identifying the enzymes-mediating chemical changes to histone tails and the DNA template, the precise regulation of gene expression remains incomplete in models of health and diabetic complications. Summary Dispelling the myth that all genomes are driven and respond equally, experimental research is now uncovering the function of enzymes conferring chromatin modifications. Whatever the role of the epigenome, showing its involvement in glycemic signaling is the first step to new strategies and targets to develop therapies that prevent, retard or reverse the long-term deleterious end-organ effects of chronic, intermittent and prior hyperglycemia.
Methyltransferase expression and tumor suppressor gene methylation in sporadic and familial colorectal cancer

Molecular mechanisms underlying coordinated hypermethylation of multiple CpG islands in cancer remain unclear and studies of methyltransferase enzymes have arrived at conflicting results. We focused on DNMT1 and DNMT3B, DNA methyltransferases responsible for (de novo) methylation, and EZH2, histone (H3K27) methyltransferase, and examined their roles in tumor suppressor gene (TSG) methylation patterns we have previously established in sporadic and familial cancers. Our investigation comprised 165 tumors, stratified by tissue of origin (117 colorectal and 48 endometrial carcinomas) and sporadic vs. familial disease (57 sporadic vs. 60 familial, mainly Lynch syndrome, colorectal carcinomas). By immunohistochemical evaluation, EZH2 protein expression was associated with a TSG methylator phenotype. DNMT1, DNMT3B, and EZH2 were expressed at significantly higher levels in tumor vs. normal tissues. DNMT1 and EZH2 expression were positively correlated and higher in microsatellite‐unstable vs. microsatellite‐stable tumors, whether sporadic or hereditary. Ki‐67 expression mirrored the same pattern. Promoter methylation of the methyltransferase genes themselves was addressed as a possible cause behind their altered expression. While DNMT1 or EZH2 did not show differential methylation between normal and tumor tissues, DNMT3B analysis corroborated the regulatory role of a distal promoter region. Our study shows that methyltransferase expression in cancer depends on the tissue of origin, microsatellite‐instability status, cellular proliferation, and—in the case of DNMT3B—promoter methylation of the respective gene. Translation of methyltransferase expression into DNA methylation appears complex as suggested by the fact that except for EZH2, no clear association between methyltransferase protein expression and TSG methylation was observed. © 2015 Wiley Periodicals, Inc.
Copy number changes of clinically actionable genes in melanoma, non‐small cell lung cancer and colorectal cancer—A survey across 822 routine diagnostic cases

Targeted deep massive parallel sequencing has been implemented in routine molecular diagnostics for high‐throughput genetic profiling of formalin‐fixed paraffin‐embedded (FFPE) cancer samples. This approach is widely used to interrogate simple somatic mutations but experience with the analysis of copy number variations (CNV) is limited. Here, we retrospectively analyzed CNV in 822 cancer cases (135 melanoma, 468 non‐small cell lung cancers (NSCLC), 219 colorectal cancers (CRC)). We observed a decreasing frequency of CNV in clinically actionable genes from melanoma to NSCLC to CRC. The overall cohort displayed 168 (20%) amplifications in 17 druggable targets. The majority of BRAF mutant melanomas (54%) showed co‐occurring CNV in other genes, mainly affecting CDKN2A. Subsets showed clustered deletions in ABL1, NOTCH1, RET or STK11, GNA11, and JAK3. Most NRAS mutant melanomas (49%) harbored CNVs in other genes with CDKN2A and FGFR3 being most frequently affected. Five BRAF/NRASwt tumors had co‐amplifications of KDR, KIT, PDGFRA and another six mutated KIT. Among all NSCLC, we identified 14 EGFRamp (with ten EGFRmut) and eight KRASamp (with seven KRASmut). KRASmut tumors displayed frequent amplifications of MYC (n = 10) and MDM2 (n = 5). Fifteen KRAS/EGFR/BRAFwt tumors had MET mutations/amplifications. In CRC, amplified IGF2 was most prevalent (n = 13) followed by MYC (n = 9). Two cases showed amplified KRAS wildtype alleles. Two of the KRASmut cases harbored amplifications of NRAS and three KRASwt cases amplification of EGFR. In conclusion, we demonstrate that our approach i) facilitates detection of CNV, ii) enables detection of known CNV patterns, and iii) uncovers new CNV of clinically actionable genes in FFPE tissue samples across cancers. © 2016 Wiley Periodicals, Inc.
Occupational Therapy Home Assessments: More than Just a Visit? An Audit of Occupational Therapy Practice in Oncology and Palliative Care

Occupational therapists at a specialist cancer centre found home assessments to be the most time-consuming intervention. To evaluate the breakdown of time and total time use for this intervention, 15 occupational therapists working in the area of oncology and palliative care participated in an audit. A total of 107 home assessments was audited. The results indicated that the total time for an average home assessment in the audit ranged between 3.31 hours and 5.59 hours. They also highlighted that the time spent in preparation and follow-up was similar to the time spent in travel and the visit itself.
Poorly differentiated thyroid cancer

Purpose of reviewPoorly differentiated thyroid carcinomas (PDTCs) comprise a small subset of heterogeneous thyroid tumors, occupying an intermediate area between well differentiated follicular or papillary carcinoma and anaplastic carcinomas, from both a histopathogenetic and a clinical point of view. PDTCs are more aggressive than the well differentiated, but less aggressive than the anaplastic thyroid cancers. They have a distinct biological behavior, and the classification of these tumors into a separate group appears justified. Recent findingsThe criteria used to diagnose PDTC have been an area of controversy. The multiple definitions of PDTC make the literature difficult to interpret. No clinical features can accurately diagnose PDTCs. Thus, the results of histocytology, immunohistochemistry, and molecular genetics tests aid in diagnosis. Given the aggressiveness of PDTCs, with increased recurrence and decreased survival rates, a multimodality treatment approach is required. SummaryWe conducted a comprehensive review of the current diagnostic and therapeutic tools in the management of patients with PDTCs. The present article aims to review the various aspects of this tumor type, from morphology to immunohistochemistry, and molecular abnormalities from a practical and daily practice-oriented point of view.
Software for generating liability distributions for pedigrees conditional on their observed disease states and covariates

For many multifactorial diseases, aetiology is poorly understood. A major research aim is the identification of disease predictors (environmental, biological, and genetic markers). In order to achieve this, a two‐stage approach is proposed. The initial or synthesis stage combines observed pedigree data with previous genetic epidemiological research findings, to produce estimates of pedigree members' disease risk and predictions of their disease liability. A further analysis stage uses the latter as inputs to look for associations with potential disease markers. The incorporation of previous research findings into an analysis should lead to power gains. It also allows separate predictions for environmental and genetic liabilities to be generated. This should increase power for detecting disease predictors that are environmental or genetic in nature. Finally, the approach brings pragmatic benefits in terms of data reduction and synthesis, improving comprehensibility, and facilitating the use of existing statistical genetics tools. In this article we present a statistical model and Gibbs sampling approach to generate liability predictions for multifactorial disease for the synthesis stage. We have implemented the approach in a software program. We apply this program to a specimen disease pedigree, and discuss the results produced, comparing its results with those generated under a more naïve model. We also detail simulation studies that validate the software's operation. Genet. Epidemiol. 34: 159–170, 2010. © 2009 Wiley‐Liss, Inc.
Association tests using kernel‐based measures of multi‐locus genotype similarity between individuals

In a genetic association study, it is often desirable to perform an overall test of whether any or all single‐nucleotide polymorphisms (SNPs) in a gene are associated with a phenotype. Several such tests exist, but most of them are powerful only under very specific assumptions about the genetic effects of the individual SNPs. In addition, some of the existing tests assume that the direction of the effect of each SNP is known, which is a highly unlikely scenario. Here, we propose a new kernel‐based association test of joint association of several SNPs. Our test is non‐parametric and robust, and does not make any assumption about the directions of individual SNP effects. It can be used to test multiple correlated SNPs within a gene and can also be used to test independent SNPs or genes in a biological pathway. Our test uses an analysis of variance paradigm to compare variation between cases and controls to the variation within the groups. The variation is measured using kernel functions for each marker, and then a composite statistic is constructed to combine the markers into a single test. We present simulation results comparing our statistic to the U‐statistic‐based method by Schaid et al. ([2005] Am. J. Hum. Genet. 76:780–793) and another statistic by Wessel and Schork ([2006] Am. J. Hum. Genet. 79:792–806). We consider a variety of different disease models and assumptions about how many SNPs within the gene are actually associated with disease. Our results indicate that our statistic has higher power than other statistics under most realistic conditions. Genet. Epidemiol. 34: 213–221, 2010. © 2009 Wiley‐Liss, Inc.