Causal inference of gene regulation with subnetwork assembly from genetical genomics data

Abstract Deciphering the causal networks of gene interactions is critical for identifying disease pathways and disease-causing genes. We introduce a method to reconstruct causal networks based on exploring phenotype-specific modules in the human interactome and including the expression quantitative trait loci (eQTLs) that underlie the joint expression variation of each module. Closely associated eQTLs help anchor the orientation of the network. To overcome the inherent computational complexity of causal network reconstruction, we first deduce the local causality of individual subnetworks using the selected eQTLs and module transcripts. These subnetworks are then integrated to infer a global causal network using a random-field ranking method, which was motivated by animal sociology. We demonstrate how effectively the inferred causality restores the regulatory structure of the networks that mediate lymph node metastasis in oral cancer. Network rewiring clearly characterizes the dynamic regulatory systems of distinct disease states. This study is the first to associate an RXRB-causal network with increased risks of nodal metastasis, tumor relapse, distant metastases and poor survival for oral cancer. Thus, identifying crucial upstream drivers of a signal cascade can facilitate the discovery of potential biomarkers and effective therapeutic targets.

Download Full-text

Preoperative Screening CT and PET/CT Scanning for Acral Melanoma: Is it Necessary?

Journal of Clinical Medicine ◽

10.3390/jcm10040811 ◽

2021 ◽

Vol 10 (4) ◽

pp. 811

Author(s):

Taketoshi Ide ◽

Takamichi Ito ◽

Maiko Wada-Ohno ◽

Masutaka Furue

Keyword(s):

Sensitivity And Specificity ◽

Clinical Signs ◽

Ct Scanning ◽

Distant Metastases ◽

Nodal Metastasis ◽

Preoperative Imaging ◽

Histopathological Analysis ◽

Preoperative Screening ◽

Acral Melanoma ◽

Pet Ct

The efficacy of preoperative imaging for acral melanoma (AM) has not been fully evaluated. We examined the accuracy of imaging modalities in the detection of nodal and distant metastases in patients with AM. A retrospective review of 109 patients with AM was performed. All patients had no clinical signs suggestive of distant metastases, and underwent preoperative screening computed tomography (CT) and positron emission tomography (PET)/CT scans. Of 100 patients without lymphadenopathy, 17 patients were suspected of having nodal metastasis in CT and PET/CT, but only two of them were confirmed on histopathological analysis. On the other hand, 12 out of 83 negatively imaged patients showed histopathological signs of nodal metastasis; thus, the sensitivity and specificity of nodal detection were 14.3% and 82.6%, respectively. Regard to the detection of distant metastases, four patients were suspected of having metastasis, but this was later ruled out. The remaining 96 negatively imaged patients were confirmed to have no metastasis at the time of CT and PET/CT by the follow-up. In contrast, distant metastases were found by CT and PET/CT in four of nine patients (44.4%) with lymphadenopathy. Routine preoperative CT and PET/CT for AM patients without lymphadenopathy may not be warranted because of low sensitivity and specificity, but it can be considered for those with lymphadenopathy.

Download Full-text

Mandibular Canal Widening and Bell’s Palsy: Sequelae of Perineural Invasion in Oral Cancer

Case Reports in Dentistry ◽

10.1155/2016/3010934 ◽

2016 ◽

Vol 2016 ◽

pp. 1-4

Author(s):

Gopinath Thilak Parepady Sundar ◽

Vishwanath Sherigar ◽

Sameep S. Shetty ◽

Shree Satya ◽

Sourabh M. Gohil

Keyword(s):

Oral Cancer ◽

Perineural Invasion ◽

Oral Submucous Fibrosis ◽

Inferior Alveolar Nerve ◽

Mandibular Canal ◽

Distinct Disease ◽

Nerve Tracts ◽

Submucous Fibrosis ◽

Neurological Disturbance ◽

Shed Light

Perineural invasion is an underrecognized route of metastatic spread along the nerve bundles within the nerve sheath into the surrounding tissues. It hinders the ability to establish local control as tumour cells can traverse along nerve tracts well beyond the extent of any local invasion rendering them inoperable and unresectable. Perineural invasion is a marker of poor prognosis. Oral submucous fibrosis with oral cancer constitutes a clinicopathologically distinct disease. Our case highlights an enigmatic presentation of oral submucous fibrosis and its coexistence with oral cancer presenting with unusual neurological disturbance of the inferior alveolar nerve and facial nerve and diffuse widening of the mandibular canal. The objective of this case report is to enumerate the significance of perineural invasion in determining the course of the disease and necessitate the need for future studies that can shed light on molecular mediators and pathogenesis of perineural spread.

Download Full-text

INDEPENDENCE IN COMPLETE AND INCOMPLETE CAUSAL NETWORKS UNDER MAXIMUM ENTROPY

International Journal of Uncertainty Fuzziness and Knowledge-Based Systems ◽

10.1142/s0218488508005571 ◽

2008 ◽

Vol 16 (05) ◽

pp. 699-713 ◽

Cited By ~ 1

Author(s):

MICHAEL J. MARKHAM

Keyword(s):

Expert System ◽

Probability Distribution ◽

Maximum Entropy ◽

Linear Constraints ◽

Causal Network ◽

Missing Information ◽

Causal Networks ◽

Small Set

In an expert system having a consistent set of linear constraints it is known that the Method of Tribus may be used to determine a probability distribution which exhibits maximised entropy. The method is extended here to include independence constraints (Accommodation). The paper proceeds to discusses this extension, and its limitations, then goes on to advance a technique for determining a small set of independencies which can be added to the linear constraints required in a particular representation of an expert system called a causal network, so that the Maximum Entropy and Causal Networks methodologies give matching distributions (Emulation). This technique may also be applied in cases where no initial independencies are given and the linear constraints are incomplete, in order to provide an optimal ME fill-in for the missing information.

Download Full-text

2847 Importance of tumor thickness using intraoral ultrasound in predicting nodal metastasis in early oral cancer

European Journal of Cancer ◽

10.1016/s0959-8049(16)31587-8 ◽

2015 ◽

Vol 51 ◽

pp. S573

Author(s):

J.R. Vishnoi ◽

S. Gupta ◽

V. Kumar ◽

N. Jamal ◽

P. Agrawal ◽

...

Keyword(s):

Oral Cancer ◽

Nodal Metastasis ◽

Tumor Thickness

Download Full-text

Multinomial modelling of TB/HIV co-infection yields a robust predictive signature and generates hypotheses about the HIV+TB+ disease state

10.1101/497842 ◽

2018 ◽

Author(s):

Fergal J Duffy ◽

Ethan G. Thompson ◽

Thomas J. Scriba ◽

Daniel E Zak

Keyword(s):

Machine Learning ◽

T Cell ◽

Nk Cell ◽

Expression Patterns ◽

Predictive Performance ◽

Cell Receptor ◽

Disease State ◽

Disease States ◽

Signature Genes ◽

Distinct Disease

AbstractBackgroundCurrent diagnostics are inadequate to meet the challenges presented by coinfection with Mycobacterium tuberculosis (Mtb) and HIV, the leading cause of death for HIV-infected individuals. Improved characterisation of Mtb/HIV coinfection as a distinct disease state may lead to better identification and treatment of affected individuals.MethodsFour previously published TB and HIV co-infection related datasets were used to train and validate multinomial machine learning classifiers that simultaneously predict TB and HIV status. Classifier predictive performance was measured using leave-one-out cross validation on the training set and blind predictive performance on multiple test sets using area under the ROC curve (AUC) as the performance metric. Linear modelling of signature gene expression was applied to systematically classify genes as TB-only, HIV-only or combined TB/HIV.ResultsThe optimal signature discovered was a single 10-gene random forest multinomial signature that robustly discriminates active tuberculosis (TB) from other non-TB disease states with improved performance compared with previously published signatures (AUC: 0. 87), and specifically discriminates active TB/HIV co-infection from all other conditions (AUC: 0.88). Signature genes exhibited a variety of transcriptional patterns including both TB-only and HIV-only response genes and genes with expression patterns driven by interactions between HIV and TB infection states, including the CD8+ T-cell receptor LAG3 and the apoptosis-related gene CERKL.ConclusionsBy explicitly including distinct disease states within the machine learning analysis framework, we developed a compact and highly diagnostic signature that simultaneously discriminates multiple disease states associated with Mtb/HIV co-infection. Examination of the expression patterns of signature genes suggests mechanisms underlying the unique inflammatory conditions associated with active TB in the presence of HIV. In particular, we observed that disregulation of CD8+ effector T-cell and NK-cell associated genes may be an important feature of Mtb/HIV co-infection.

Download Full-text

Pattern of Lymph Node Metastasis in Oral Cancer

Journal of Dhaka Medical College ◽

10.3329/jdmc.v29i1.51170 ◽

2021 ◽

Vol 29 (1) ◽

pp. 41-46

Author(s):

Mahmud Asif Rifat ◽

Mostafa Kamal Arefin ◽

Abu Yusuf Fakir ◽

SK Nurul Fattah Rumi ◽

Husne Qumer Osmany ◽

...

Keyword(s):

Lymph Node ◽

Lymph Node Metastasis ◽

Oral Cancer ◽

Nodal Metastasis ◽

Oral Carcinoma ◽

Medical College ◽

Cancer Management ◽

Node Metastasis ◽

Floor Of The Mouth ◽

Level I

Background: Oral cancer is a common neoplasm worldwide which has a increased incidence and mortality rate over the past decades. In spite of skilled surgical and radio therapeutic modalities it is characterized by poor prognosis and a low survival rate. Lymph node metastasis is an important negative prognostic factor in oral cancer. In this study, pattern of cervical lymph node metastasis in oral carcinoma has been described. Such information may contribute to the understanding of oral cancer management plan. Methods: This cross-sectional observational study was conducted in the Otolaryngology and Head-Neck surgery department of Dhaka Medical College Hospital. The study period was from January 2018 to June 2018. A total of 50 patients were selected by purposive sampling technique. Data were collected by study physician himself. Then these collected data were recorded in structured case report forms. Clinical examination and relevant investigations were done. After planned surgical procedure post operative histopathological reports were collected. All collected questionnaire were checked very carefully. Data were processed and analyzed with the help of computer program SPSS and Microsoft excel. Quantitative data were expressed as mean and standard deviation and qualitative data as frequency and percentage. Comparison were done by tabulation and graphical presentation in the form of tables, pie chart, graphs, bar diagrams, histogram & charts etc. Result: Overall demographic features of 50 patients revealed that, the maximum incidence was seen in the age group 31-50 years (54.0%), mean age of the patient was 49.6 ±9.2 year. Male and female ratio was 4.5:1. In this study most of the tumors were well and moderately differentiated, 34.0% and 62.0% respectively. Aetiology and predisposing factors revealed that the most common were cigarette smoking, betal quid and alcohol consumption, present in 52.0%, 28.0% and 22.0% of patients respectively. Post operative histopathology reports showed that 24 patients (48.0%) had neck node metastasis among which 59.4% were with tumor size >1 cm. Tumors with the depth of invasion >3 mm had a very high risk of metastasis (P<0.0001), as compared to tumor less than 3 mm in thickness. Out of the 24 patients with nodal metastasis 17(34.0%) patients had a single node metastasis (N1). Level I and Level II were the commonest site to be involved (14 patients). Nodal metastasis predominantly occurred from primary tumour site of tongue (22.0%) and floor of the mouth (14.0%). It was seen that patients with higher grade had a higher risk of metastasis (grade 1:–29.4%, grade 2:- 54.8%, grade 3:– 100.0%). Conclusion: Oral carcinoma may appear at any sub site, although there are certain areas in which it is found more frequently, such as the oral tongue, cheek and floor of the mouth. Lymph node metastasis is more common in oral carcinoma mostly level I & II, which is one of the most relevant prognostic factors. Elective neck dissection can be considered in all patients with tumors more than 3 mm in thickness. J Dhaka Medical College, Vol. 29, No.1, April, 2020, Page 41-46

Download Full-text

Social work education: learning from the past?

Social Work ◽

10.1332/policypress/9781447356530.003.0006 ◽

2020 ◽

pp. 77-96

Author(s):

Hilary Tompsett

Keyword(s):

Social Work ◽

Social Services ◽

Regulatory Structure ◽

Competitive Tendering ◽

Institutional Instability ◽

Regulatory Systems ◽

Best Value ◽

History Of ◽

High Regard ◽

Work Education

The history of the regulation of the personal social services from 1970 onwards is described, contextualised and analysed. The various purposes and styles of inspection within regulatory systems are identified and discussed. The effects and contributions of competitive tendering of services, the Performance Assessment Framework, Joint Reviews, Best Value and Special Measures are noted. Adverse criticisms in the late 1980s of the Social Services Inspectorate, established in 1985, are contrasted with the high regard in which the Inspectorate was held by the late 1990s. The chapter then sets out the subsequent rapid changes to the regulatory structure in the years 2004-2010.The campaign for the registration of social workers, leading to the establishment in 2001 of the General Social Care Council, and its subsequent replacement first by the Health and Care Professions Council and then by Social Work England, is also discussed.The chapter compares unfavourably the experience in England, with its chronic institutional instability, with those of Scotland, Wales and Northern Ireland, which have been characterised by more constructive partnerships.

Download Full-text

How, with whom and when: an overview of CD147-mediated regulatory networks influencing matrix metalloproteinase activity

Bioscience Reports ◽

10.1042/bsr20150256 ◽

2016 ◽

Vol 36 (1) ◽

Cited By ~ 44

Author(s):

G. Daniel Grass ◽

Bryan P. Toole

Keyword(s):

Matrix Metalloproteinase ◽

Regulatory Networks ◽

Protein Transport ◽

Distant Metastases ◽

Drug Transporter ◽

Regulatory Systems ◽

Membrane Bound ◽

Membrane Type ◽

Tumour Initiation ◽

Metalloproteinase Activity

Matrix metalloproteinases (MMPs) comprise a family of 23 zinc-dependent enzymes involved in various pathologic and physiologic processes. In cancer, MMPs contribute to processes from tumour initiation to establishment of distant metastases. Complex signalling and protein transport networks regulate MMP synthesis, cell surface presentation and release. Earlier attempts to disrupt MMP activity in patients have proven to be intolerable and with underwhelming clinical efficacy; thus targeting ancillary proteins that regulate MMP activity may be a useful therapeutic approach. Extracellular matrix metalloproteinase inducer (EMMPRIN) was originally characterized as a factor present on lung cancer cells, which stimulated collagenase (MMP-1) production in fibroblasts. Subsequent studies demonstrated that EMMPRIN was identical with several other protein factors, including basigin (Bsg), all of which are now commonly termed CD147. CD147 modulates the synthesis and activity of soluble and membrane-bound [membrane-type MMPs (MT-MMPs)] in various contexts via homophilic/heterophilic cell interactions, vesicular shedding or cell-autonomous processes. CD147 also participates in inflammation, nutrient and drug transporter activity, microbial pathology and developmental processes. Despite the hundreds of manuscripts demonstrating CD147-mediated MMP regulation, the molecular underpinnings governing this process have not been fully elucidated. The present review summarizes our present knowledge of the complex regulatory systems influencing CD147 biology and provides a framework to understand how CD147 may influence MMP activity.

Download Full-text

Determination of Cervical Metastases by Lymphoscintigraphy in Patients with Oral Cancer: A Single Institute Experience

Bangladesh Journal of Nuclear Medicine ◽

10.3329/bjnm.v21i1.40244 ◽

2019 ◽

Vol 21 (1) ◽

pp. 12-15

Author(s):

Md Ahsan Habib ◽

Quazi Billur Rahman ◽

Pupree Mutsuddy ◽

Shamim MF Begum ◽

Sadia Sultana ◽

...

Keyword(s):

Lymph Node ◽

Oral Cancer ◽

Predictive Value ◽

Cervical Lymph Node Metastasis ◽

Lymph Node Involvement ◽

Nodal Metastasis ◽

Histopathological Diagnosis ◽

Regional Lymph Nodes ◽

Oral Cancer Patients ◽

Lymphatic Obstruction

Background: Oral cancer is the sixth most common cancer in the world. Cervical metastasis is an important adverse prognostic factor and about 40% of the patients with oral cancer develop lymphatic metastasis. Lymphoscintigraphy is the minimally invasive method for the detection of cervical nodal metastasis. The aim of the study was to detect the lymphatic involvement with the aid of lymphoscnitigraphy in patient with oral cancer undergoing surgical procedure and to find out the accuracy of the findings with the post operative histopathological diagnosis. Patients and methods: A total of 30 patients with histologically proven oral cancer underwent lymphoscintigraphic evaluation to detect the lymphatic spread of the tumor. The findings and results of lymphoscintigraphy were compared with the postoperative histopathological diagnosis. Results: Among the 30 patients, lymphatic obstruction was observed in 19 patients of whom 15 patients had perfusion defect and 4 patients had gap defect. No lymphatic obstruction was evident in the rest 11 patients by lymphoscintigraphy. The calculated sensitivity of lymphoscintigraphy in diagnosis of cervical lymph node metastasis was 100%, specificity 78.6%, accuracy 90% and positive predictive value was 84.2% and negative predictive value was 100%. Conclusion: Lymphoscintigraphy was found to be an effective method in detecting lymph node involvement and can be used as an alternative to identify regional lymph nodes metastases pre-operatively in oral cancer patients. Thereby, it will help the surgeon to plan the extent of dissection before surgery which may decrease postoperative complications related to unnecessary extensive lymph node dissection and morbidity. Bangladesh J. Nuclear Med. 21(1): 12-15, January 2018

Download Full-text