Automated analysis of immunohistochemistry images identifies candidate location biomarkers for cancers

Molecular biomarkers are changes measured in biological samples that reflect disease states. Such markers can help clinicians identify types of cancer or stages of progression, and they can guide in tailoring specific therapies. Many efforts to identify biomarkers consider genes that mutate between normal and cancerous tissues or changes in protein or RNA expression levels. Here we define location biomarkers, proteins that undergo changes in subcellular location that are indicative of disease. To discover such biomarkers, we have developed an automated pipeline to compare the subcellular location of proteins between two sets of immunohistochemistry images. We used the pipeline to compare images of healthy and tumor tissue from the Human Protein Atlas, ranking hundreds of proteins in breast, liver, prostate, and bladder based on how much their location was estimated to have changed. The performance of the system was evaluated by determining whether proteins previously known to change location in tumors were ranked highly. We present a number of candidate location biomarkers for each tissue, and identify biochemical pathways that are enriched in proteins that change location. The analysis technology is anticipated to be useful not only for discovering new location biomarkers but also for enabling automated analysis of biomarker distributions as an aid to determining diagnosis.Our understanding of the number and types of changes that occur in various cancers is continuously growing. Previous work to discover proteins that vary significantly between normal and cancer cells has used techniques such as microarray profiling, next-generation sequencing, antibody arrays, and proteomic profiling (1–4). These studies have led to the discovery of proteins (termed expression biomarkers) whose expression levels mark different disease states. However, for some proteins, the extent of localization in the nucleus can be used to predict patient prognosis; β-catenin (5) and NF-κB (6) are examples. The discovery of more proteins that undergo oncogenesis-associated changes in subcellular location (which we term location biomarkers) could potentially improve disease diagnosis in conjunction with traditional protein expression markers. Further, discovering proteins that relocate in the disease state may give new insight into changes driving disease, and such changes would go undetected by measuring only expression.Immunohistochemistry (IHC) studies are a major source of data on protein expression and location. Most such studies use visual examination to assess changes, a difficult and time-consuming task. With the advent of high-throughput acquisition technologies like tissue microarrays and automated slide scanners, computerized analysis of tissue images is highly desirable, and studies have shown that quantitative software can detect changes in disease states that are missed by visual inspection (7). Methods for analyzing changes in expression and pattern are well established in cultured cells (8), but histological images are typically more difficult to analyze because cellular heterogeneity and the closely packed organization of cells lead to significant cell segmentation challenges. Several projects have been initiated to build workflows that process IHC images (9, 10). Most of this work has been focused on quantifying differences in protein abundance between normal and cancer tissue. However, as discussed earlier, differences in subcellular protein locations could also be critical for understanding and diagnosing disease. Thus, there is a strong need for systems that can analyze protein subcellular location in IHC images.We have previously described an automated system for recognizing major subcellular patterns in IHC images (11), and presented preliminary results from the use of that system to identify proteins that change location in various cancers (12). These studies used a subset of the extensive collection of IHC images in the Human Protein Atlas (HPA) (13). However, we have found that the performance on a larger collection of proteins with more pattern variation was significantly lower compared with the 16 marker proteins used in our previous study. We therefore sought to develop a system that can identify potential location biomarkers by using new approaches without explicit classification. By using images from the HPA, we show that our system can identify proteins with altered subcellular location directly from tissue images and anticipate that approaches such as this may significantly contribute to diagnosis, treatment, and monitoring of cancers.     

Achalasia and Down syndrome: a unique association not to be missed

Achalasia is a rare primary oesophageal motility disorder that presents as a functional obstruction at the oesophago-gastric junction. The prevalence of achalasia in Down syndrome is much higher, which implies a unique association between these two uncommon conditions. Although the exact aetiology of achalasia is unknown, studies have proposed that its pathogenesis is related to autoimmune, infectious or genetic factors, leading to the intrinsic loss of inhibitory myenteric neurons in both the oesophagus and lower oesophageal sphincter. We herein report the case of a 16-month-old girl with Down syndrome and achalasia who was initially treated for gastro-oesophageal reflux disease. The diagnosis of achalasia was made only when her condition deteriorated, with subsequent failure to thrive, and upon further investigations, including barium swallow study and upper endoscopy. We also review the various mechanisms postulated in the development of achalasia in Down syndrome, as well as the various treatment modalities available for this rare disorder.     

Differentiated thyroid carcinomas with vascular invasion: a comparative study of follicular,Hürthle cell and papillary thyroid carcinoma

AIM: Non-medullary thyroid carcinomas arise from follicular cells. The purpose of this study is to correlate clinical and pathological properties of these tumours with the rate of distant metastasis from a series of thyroid tumours excised at one institution. METHODS: A total of 311 non-medullary thyroid tumours were identified and divided into: 29 follicular carcinoma (FC), 12 Hürthle cell carcinoma (HC), 13 Hürthle cell papillary thyroid carcinoma (HPTC) with vascular invasion (VI), 32 papillary thyroid carcinoma (PTC) with VI and 225 PTC without VI. The mean follow-up was 6.5 years with a range of 1-17 years. The tumours were histologically subdivided into minimal or wide invasion for FC and HC and focal or extensive invasion for PTC and HPTC, and stratified according to status of VI. RESULTS: The rate of distant metastasis was similar for FC, malignant Hürthle cell tumours and PTC with VI, and increased with extent of invasion. VI was seen in 12% of all PTC and 0% of HPTC in this study. PTC without VI were associated with a much lower potential of distant metastasis, were smaller in size and occurred in patients of younger age than PTC with VI. In addition, there was a tendency for increased potential for distant metastases with increased tumour size and patient age for all groups of tumours in the study. Patient age and tumour size appeared to play a smaller role than that of VI in predicting distant metastasis. CONCLUSIONS: Our study suggests that the rate of distant metastasis relates to VI, patient age and tumour size, regardless of Hürthle cell, FC or PTC differentiation. PTC of large size, and in patients older than 45 years, have a high propensity for vascular invasion.     

Docosahexaenoic acid supplementation in age-related cognitive decline: a systematic review and meta-analysis

European Journal of Clinical Pharmacology - To investigate the role of DHA supplementation in preventing age-related cognitive decline (ARCD) in individual cognitive domains by conducting...     

Anaesthesia in Barbados

Purpose  To describe the anaesthesia services in Barbados: to present the major challenges confronting the Anaesthesia Department of the govemment-owned Queen Elizabeth Hospital (QEH): and to describe the Department’s approaches to optimise safety and cost-effectiveness of anaesthesia at QEH. Source of Information  Authors (KBS, HSLM. RAH), who collectively provided more than 50 yr of anaesthesia at QEH; the Dean (ERW) of the University of West Indies Medical School (Barbados campus); archives of Barbados; and records of QEH. Principal findings  The government of Barbados provides modem health care services to all of its citizens, primarily at QEH. Barbados, however, has tight financial constraints, infrastructura) limitations, and a bureaucratic administration that predispose QEH’s Anaesthesia Department to unexpected depletions of drugs and disposable supplies, sporadic shortages of personnel and functioning equipment, and occasional quality assurance problems. To deal with such problems, the Anaesthesia Department has implemented several pro-active measures; establishing an audit system to prevent depletion of imported drugs and supplies: training local personnel to maintain equipment: purchasing an oxygen concentrator to reduce oxygen costs: decreasing nitrous oxide use (expensive m Barbados): and initiating its own quality and safety standards. Conclusion  Continuous delivery of high quality, cost-effective anaesthesia care requires thoughtful planning by administrators and judicious resource allocations. Health care administrators and clinical departments need to work together closely to establish a framework that enables departments to play a major role in determining how the institution’s limited financial resources are best allocated to meet the departmental pnonties.

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Résumé Objectif  Decnre I’organisation de I’anesthesie a la Barbade; presenter les problemes considerables auxquels doit faire face le departement d’anesthesie de I’hdpital d’etat Queen Elizabeth (QEH) et decnre les efforts du departement pour optimahser la securite et lefficabte en fonction des couts. Source de l’information  Les auteurs (KBS. HSLM. RAH) qui ont collectivement foumi plus de 50 ans d’anesthesie au QEH; le doyen de la faculte de medecine des Antilles (campus de la Barbade); les archives de la Barbade; les dossiers du QEH. Principales constatations  Le gouvemement de la Barbade procure des services sanrtaires modemes a tous ses citoyens, pnncipalement au QEH. La Barbade subit toutefois des contraintes financieres tres severes. des limitations dans son infrastructure et une bureaucratie qui predispose le departement d’anesthesie du QEH a des penunes imprevisibles de medicaments et de materiel jetabte. a I’absenteisme du personnel et au manque d’equipement spoi adique. et a des problemes occasionnels d’assurance-qualite. Raur regler ces genres de problemes, le departement d’anesthesie a mis en vigueur plusieurs mesures simultanees; I’etablissement d’un systeme de comptabilite pour prevemr les penunes de medicaments et du materiel importes; la formation de personnel pour la maintenance de r^quipement; I’achat dun concentrateurpour reduire lecout de I’oxygene; la rationnement du protoxyde d’azote (cher a la Barbade); et le mise en vigueur de ses propres standards de qualrte et de seurrte. Conclusion  La prestation continue de sans anesthestque efficients et de haute qualrte requiert une plantation soignee et I’allocation judicieuse de ressources. Les administrateurs en soins de sante et les departements dmiques doivent travailler de concert pour etablir un encadrement permettant aux departements de jouer un role majeur dans I’allocation de ressources financieres limitees en tenant compte des pnorites etabhes par les departements.