Autoimmune regulator and self-tolerance – molecular and clinical aspects

The establishment of central tolerance in the thymus is critical for avoiding deleterious autoimmune diseases. Autoimmune regulator (AIRE), the causative gene in autoimmune polyendocrine syndrome type-1 (APS-1), is crucial for the establishment of self-tolerance in the thymus by promoting promiscuous expression of a wide array of tissue-restricted self-antigens. This step is critical for elimination of high-affinity self-reactive T cells from the immunological repertoire, and for the induction of a specific subset of Foxp3⁺ T-regulatory (T_reg) cells. In this review, we discuss the most recent advances in our understanding of how AIRE operates on molecular and cellular levels, as well as of how its loss of function results in breakdown of self-tolerance mechanisms characterized by a broad and heterogeneous repertoire of autoimmune phenotypes.     

Epidemiological,clinical and control investigations on field porcine coccidiosis: clinical,epidemiological and parasitological paradigms?

For several reasons, we are convinced that the parasitologist community must look again at porcine neonatal coccidiosis. We find it surprising that this disease is seldom addressed, and that assumptions are not always supported by clinico-epidemiological analysis. For example, the relationship between diarrhoea and the excretion of oocysts during experimental infection versus field infection is not questioned. Lindsay et al. review parasitological knowledge of this disease in the latest (1999) edition of Diseases of swine. Although this paper is divided into two parts, we have three distinct objectives: (1) to bring to the debate our experience in the medical control of this disease; (2) to propose a diagnostic methodology; (3) to raise some questions on various clinical, epidemiological and parasitological unknowns. Received: 2 February 2000 / Accepted: 4 February 2000     

Tuberculosis of the head and neck – epidemiological and clinical presentation

Introduction

The aim of our retrospective study was to review the clinical and epidemiological presentation of head and neck tuberculosis.

Material and methods

We analyzed the history of 73 patients with head and neck tuberculosis hospitalized in the Department of Otolaryngology, Medical University of Warsaw, between 1983 and 2009.

Results

We found that 26 (35.6%) patients presented with lymph node tuberculosis, 20 (27.4%) with laryngeal tuberculosis, 10 (13.7%) with oropharyngeal tuberculosis, 9 (12.3%) with salivary gland tuberculosis, 3 (4.1%) with tuberculosis of paranasal sinuses, 3 (4.1%) with aural tuberculosis, and 2 (2.7%) with skin tuberculosis in the head and neck region. Within the group of patients with lymph node tuberculosis in 15 cases there were infected lymph nodes of the 2^nd and 3^rd cervical region and in 11 infected lymph nodes of the 1^st cervical region. In 5 cases of laryngeal tuberculosis there was detected coexistence of cancer. Oropharyngeal tuberculosis in 7 cases was localized in tonsils, where in 1 case coexisting cancer was diagnosed. Chest X-ray was performed in all cases and pulmonary tuberculosis was identified in 26 (35.6%) cases.

Conclusions

We conclude that tuberculosis still remains a problem and must be taken into consideration in the diagnostic process. The coincidence of tuberculosis and cancer is remarkable in the head and neck region.     

EMT and MET in carcinoma—clinical observations,regulatory pathways and new models

EMT and MET in carcinoma-clinical observations, regulatory pathways and new models.     

Protein analysis of tissues—current views and clinical perspectives

Proteomics raises high expectations in finding novel and reliable biomarkers for diagnosis, prognosis and therapy prediction. The goal of the 2-day workshop “Protein analysis of tissues—current views and clinical perspectives” was to bring together scientists from multiple areas of protein research interested in tissue analysis.     

Detecting EGFR alterations in clinical specimens—pitfalls and necessities

We investigated the epidermal growth factor receptor (EGFR) status in early stage lung cancer in Southern Sweden, a population for which there are no previous reports on the EGFR mutation frequency. Three hundred fifty small cell lung cancers, adenocarcinomas (AC), squamous cell carcinomas (SqCC), and large cell carcinomas were analyzed using a combination of techniques for the analysis of protein expression, gene copy numbers, and mutations. Immunohistochemical (IHC) staining with antibodies for the EGFR mutations L858R and del E746-A750 revealed intratumoral heterogeneity and several discrepant cases when compared to mutation-specific polymerase chain reaction (PCR)-based analysis. The frequencies of these two mutations, when considering IHC staining with mutation-specific antibodies in a cohort of 298 cases and subsequent confirmation by PCR, were 10 % in AC and <2 % in SqCC. Furthermore, screening by sequencing of EGFR in a cohort of 52 lung AC and squamous carcinomas demonstrated a more diverse mutation spectrum, not covered by the mutation-specific antibodies. High expression of total EGFR protein was correlated to high gene copy numbers but did not reflect the mutational status of the tumors. We believe that the mutation spectra in a Southern Swedish population is too diverse to be covered by the mutation-specific antibodies, and we also raise some other issues regarding the use of the mutation-specific antibodies, for example concerning heterogeneous expression of the mutated protein, optimal antibody dilution, and discrepancies between staining results and PCR.     

Artificial intelligence in clinical multiparameter flow cytometry and mass cytometry–key tools and progress

There are many research studies and emerging tools using artificial intelligence (AI) and machine learning to augment flow and mass cytometry workflows. Emerging AI tools can quickly identify common cell populations with continuous improvement of accuracy, uncover patterns in high-dimensional cytometric data that are undetectable by human analysis, facilitate the discovery of cell subpopulations, perform semi-automated immune cell profiling, and demonstrate potential to automate aspects of clinical multiparameter flow cytometric (MFC) diagnostic workflow. Utilizing AI in the analysis of cytometry samples can reduce subjective variability and assist in breakthroughs in understanding diseases.Here we review the diverse types of AI that are being applied to clinical cytometry data and how AI is driving advances in data analysis to improve diagnostic sensitivity and accuracy. We review supervised and unsupervised clustering algorithms for cell population identification, various dimensionality reduction techniques, and their utilities in visualization and machine learning pipelines, and supervised learning approaches for classifying entire cytometry samples.Understanding the AI landscape will enable pathologists to better utilize open source and commercially available tools, plan exploratory research projects to characterize diseases, and work with machine learning and data scientists to implement clinical data analysis pipelines.     

Expression of RORα in gastric cancer and clinical pathological significance

目的 观察维甲酸相关孤核受体α(Retinoid acid receptor related Orphan Receptor α,RORα)蛋白在胃癌中的表达,探讨其与胃癌发生、发展的关系,为寻找胃癌肿瘤标记物提供一定的实验依据.方法 应用组织芯片技术及免疫组化SP法检测90例胃癌组织、48例癌旁胃黏膜组织与22例正常胃黏膜组织中RORα的表达,研究RORα与胃癌发生、发展的关系.结果 RORα蛋白在胃癌组织中表达下调,正常胃黏膜、癌旁胃黏膜和胃癌组织中RORα蛋白阳性率分别为83.36%(19/22),56.25%(27/48)和24.44%(22/90),3者相比差异有显著性(P＜0.05).高分化腺癌、中分化腺癌、低分化腺癌、黏液腺癌和印戒细胞癌中,RORα阳性率分别为45.00%(9/20)、27.59%(8/29)、14.29%(3/21)、11.11%(1/9)和9.05%(1/11).高分化腺癌RORα阳性率高于低分化腺癌(P＜0.05).结论 RORα蛋白下调与胃癌的发生、发展相关,且可能与胃癌的分化程度有关.     

The doctor and the patient--how is a clinical encounter perceived?

Objective

To examine the population distribution of different types of relationships between people with chronic conditions and their doctors that influence decisions being made from a shared-decision making perspective.

Methods

A survey questionnaire based on recurring themes about the doctor/patient relationship identified from qualitative in-depth interviews with people with chronic conditions and doctors was administered to a national population sample (n = 999) of people with chronic conditions.

Results

Three factors explained the doctor/patient relationship. Factor 1 identified a positive partnership characteristic of involvement and shared decision-making; Factor 2 doctor-controlled relationship; Factor 3 relationship with negative dimensions. Cluster analysis identified four population groups. Cluster 1 doctor is in control (9.7% of the population); Cluster 2 ambivalent (27.6%); Cluster 3 positive long-term relationship (58.6%); Cluster 4 unhappy relationship (4.4%). The proportion of 18-34 year olds is significantly higher than expected in Cluster 4. The proportion of 65+ year olds is significantly higher than expected in Cluster 1, and significantly lower than expected in Cluster 4.

Conclusion

This study adds to shared decision-making literature in that it shows in a representative sample of people with chronic illnesses how their perceptions of their experiences of the doctor-patient relationship are distributed across the population.

Practice implications

Consideration needs to be given as to whether it is better to help doctors to alter their styles of interactions to suit the preferences of different patients or if it is feasible to match patients with doctors by style of decision-making and patient preference.     

How do academic health centers value and encourage clinical research?

To investigate whether there is a misalignment of the perceived values of and incentives for clinical research within U.S. academic health centers (AHCs), in 1999 the authors surveyed medical school deans, academic administrators, department chairs, and faculty members at 80 AHCs that are the members of the University HealthSystem Consortium, a not-for-profit consortium of AHCs. A total of 358 faculty from 58% of the institutions surveyed responded, with a mean of 3.76 responses/institution. There was general agreement that clinical research offers AHCs a considerable spectrum of benefits, including prestige, recruitment and retention of faculty, criteria for promotion of faculty, and financial support. Investigator-initiated research and government-funded research ranked highest in terms of their desirability compared with industry-sponsored and contract research. This preference was agreed upon across all categories of respondents and types of research (translational, clinical tests, and outcomes). Significant differences existed between the perceptions of deans/AHC administrators, who stated that they were increasing their emphasis on clinical investigation in the areas of research space (56% of responders), administrative support (81%), and patient recruitment (61%) and the perceptions of their departmental chairs/faculties in the same areas (34%, 52%, and 40%, respectively; p <.05). Faculty opinions documented few new investments in the actual infrastructure dedicated to clinical research. The authors conclude that their findings, which they consider reasonably representative, strongly suggest that the value of clinical research to AHCs is well understood. Their findings also identify important opportunities for AHCs to provide a wider range of incentives for the conduct of clinical research.     

Pathogenetic role and clinical significance of interleukin-1β in cancer

In recent years, pro-oncogenic mechanisms of the tumour microenvironment (ТМЕ) have been actively discussed. One of the main cytokines of the TМЕ is interleukin-1 beta (IL-1β), which exhibits proinflammatory properties. Some studies have shown an association between an increase in IL-1β levels and tumour progression. The purpose of this review is to analyse the pathogenic mechanisms induced by IL-1β in the TМЕ, as well as the diagnostic significance of the presence of IL-1β in patients with cancer and the efficacy of treatment with IL-1β inhibitors. According to the literature, IL-1β can induce an increase in tumour angiogenesis due to its effects on the differentiation of epithelial cells, pro-angiogenic molecule secretion and expression of adhesion molecules, thus increasing tumour growth and metastasis. IL-1β is also involved in the suppression of anti-tumour immune responses. The expression and secretion of IL-1β has been noted in various types of tumours. In some clinical studies, an elevated level of IL-1β was found to be associated with low efficacy of anti-cancer therapy and a poor prognosis. In most experimental and clinical studies, the use of IL-1β inhibitors contributed to a decrease in tumour mass and an increase in the response to anti-tumour drugs.     

Expression and regulation of the ΔN and TAp63 isoforms in salivary gland tumorigenesis clinical and experimental findings

The TP63 gene, a TP53 homologue, encodes for two main isoforms by different promoters: one retains (TA) and the other lacks (ΔN) the transactivation domain. p63 plays a critical role in the maintenance of basal and myoepithelial cells in ectodermally derived tissues and is implicated in tumorigenesis of several neoplastic entities. However, the biological and regulatory roles of these isoforms in salivary gland tumorigenesis remain unknown. Our results show a reciprocal expression between TA and ΔN isoforms in both benign and malignant salivary tumors. The most dominantly expressed were the ΔN isoforms, whereas the TA isoforms showed generally low levels of expression, except in a few tumors. High ΔNp63 expression characterized tumors with aggressive behavior, whereas tumors with high TAp63 expression were significantly smaller and less aggressive. In salivary gland cells, high expression of ΔNp63 led to enhanced cell migration and invasion and suppression of cell senescence independent of TAp63 and/or TP53 gene status. We conclude the following: i) overexpression of ΔNp63 contributes to salivary tumorigenesis, ii) ΔNp63 plays a dominant negative effect on the TA isoform in the modulation of cell migration and invasion, and iii) the ΔN isoform plays an oncogenic role and may represent an attractive target for therapeutic intervention in patients with salivary carcinomas.     

Anorectal functions after perineal and retropubic radical prostatectomy – a prospective clinical and anal manometric assessment

Introduction

The aim of this study is to evaluate the anorectal functions of prostate cancer patients who have undergone radical perineal prostatectomy (RPP) or radical retropubic prostatectomy (RRP) surgery.

Material and methods

Thirty-seven patients with an indication for radical prostatectomy were included after informed consent. Anorectal manometry was performed before and one month after the surgery in 22 RPP and 15 RRP patients in our clinic. Clinical assessment was evaluated by anorectal functions with anal incontinence scoring (AIS) (Fernandez; no incontinence = 0; maximal incontinence = 12). Patients with a history of anorectal surgery were excluded from the study. The following data were recorded: external anal sphincteric pressure (EASP), internal anal sphincteric pressure (IASP), minimum ano-rectal reflex volume (MARRV) and minimum rectal sensory volume (MRSV).

Results

In the RPP and RRP groups, the mean age was 66 (56-75) and 64.3 (52-73) years, respectively. In the RPP group, EASP and IASP values showed a significant decrease after the surgery. In the RRP group, EASP and IASP were also decreased after the surgery, but without statistical significance. No significant change was seen in MARRV and MRSV of either group. When the scores of AIS were analysed, no significant clinical difference between pre- or post-operative scores was seen in RPP and RRP groups.

Conclusions

Perineal or retropubic surgery may injure pelvic floor muscles and/or supplying nerves, which likely causes anorectal dysfunction. Although there is a significant decrease in early postoperative EASP and IASP after RPP, it has no clinical significance according to AIS.     

Expression and clinical significance of CD151 and integrin α3β1 in colorectal tumors

目的:探讨CD151和整合素α3β1在直肠腺瘤及结直肠腺癌组织中的表达及其与临床各个病理因素之间的关系,并且研究两者的相关性.方法:应用免疫组织化学双染方法对正常结直肠黏膜、结直肠腺瘤及结直肠腺癌组织各120例进行CD151和整合素α3β1检测,并进行Kaplan-Meier生存分析.采用Spearman等级相关分析CD151和整合素αβ1之间的相关性.结果:CD151结直肠正常黏膜、腺瘤、腺癌组织的阳性率分别为21.7％、52.5％、72％,腺瘤和腺癌组织分别与正常黏膜比较均具有统计学意义.整合素α3β1在结直肠正常黏膜、腺瘤、腺癌组织的阳性率分别为34.2％、55％、70％,腺瘤和腺癌组织分别与正常黏膜比较均具有统计学意义.在结直肠腺癌中,CD151和整合素α3β1的表达与患者年龄、性别和肿瘤的部位、大小无相关性,与肿瘤的分化程度、浸润深度、淋巴结转移及Duke's分期有关.CD151和整合素α3β1在大肠正常黏膜、腺瘤及腺癌组织中的表达经双变量相关分析,表达呈正相关.从图的Kaplan-Meier生存曲线及Log-Rank检验可知,CD151+、α3β1+、CD151+α3β1+与大肠癌患者5年生存期密切相关,是影响大肠癌预后的因素.结论:CD151和整合素α3β1在大肠癌的表达密切相关,提示CD151与整合素α3β1复合物存在于大肠癌,其表达对预后产生明显的影响.CD151与整合素α3β1联合表达是临床预后判断的可靠指标.