Biomedical subjects

O Eremin

Publications and source records attributed to O Eremin.

At least 19 recordsLinked to original sources

PubMed2006

Vaccination therapy in malignant disease.

Improvement in survival among patients with early malignancy is well established in various cancers. However, long-term survival in those with advanced malignancy has changed little and this poses a major therapeutic challenge to clinicians. Anti-cancer immunotherapy is a novel approach, which is still experimental, but offers a new therapeutic strategy. In this review, we discuss the basic immunological interplay between the host immune system and the tumour, mechanisms of anti-tumour immune responses induced by immunotherapy and key in vivo pilot studies of active specific immunotherapy in various sold cancers, carried out during the last five years.

Cancer Vaccines↗

PubMed2006

Dendritic cell biology, dysfunction and immunotherapy in gastrointestinal cancers.

Gastrointestinal (GI) cancers make up a significant proportion of newly diagnosed malignant disease. The five-year survival for these GI cancers is poor. Anti-cancer host defences are thought to play a role in these cancers, albeit they are suboptimal. Novel immunotherapies are being introduced to treat such patients. This review describes basic cell biology of dendritic cells, as they are thoughtto play a key role in generating effective anti-tumour responses. Dendritic cell dysfunction in patients with various cancers is documented and immunotherapy using dendritic cells in a range of GI cancers is described and discussed

Dendritic Cells↗

PubMed2006

Neoadjuvant chemotherapy in women with large and locally advanced breast cancer: chemoresistance and prediction of response to drug therapy.

Patients with large and locally advanced breast cancer (LLABC) present with a therapeutic challenge and undergo multimodality treatment. Many such patients receive neoadjuvant chemotherapy (NAC) prior to surgery. However, a number of these patients do not respond well to NAC and only a percentage (usually less than 30%) obtains a complete or optimal response. A range of mechanisms are believed to be involved in this chemoresistance, including ATP binding cassette (ABC) transporter overexpression, dysregulation of apoptosis and possibly increased numbers of cancer stem cells. The chemoresistant processes may be due to more than one mechanism. The ability to predict a response to NAC would be beneficial, targeting expensive and toxic drug treatment to those likely to respond and providing a therapeutic strategy for further post-operative chemotherapy. Currently, many biomarkers have been studied with a view to establishing a predictor of response. However, no single biomarker appears to be effective. Genomics is a novel biotechnological process which is being used to predict response to drug therapy; this work is currently at an early stage of development

Antineoplastic Agents↗

PubMed2005

Vaccination and malignant disease: promising therapeutic approach.

Immunotherapy of cancer is now entering its second century. Much of our understanding of the complex interaction between tumours and the host immune system has come about because of technological and immunobiological advances in very recent years. For some malignancies, such as bladder cancer and malignant melanoma, immunotherapy is becoming an accepted form of adjuvant therapy. However, for most types of cancer, immunotherapy remains experimental and the majority of surgeons will have had little experience of immunotherapy in the clinical setting. This review provides a background to the scientific basis of immunotherapy, how different forms of immunotherapy are delivered and how their effects are monitored.

Antigens, Neoplasm↗

PubMed2004

Immunological aspects of head and neck cancer: biology, pathophysiology and therapeutic mechanisms.

Advanced cancer and head and neck cancer, in particular, remains a major clinical challenge with its associated morbidity and inevitable mortality. Local control of early disease is achievable in many solid tumours with current surgical and radiotherapeutic techniques but metastatic disease is associated with poor outcome and prognosis. It is known that, by the time of presentation, many patients will already have occult microscopic metastatic disease, and surgery and radiotherapy will not result in long-term survival. What little effect modern chemotherapeutic agents have on microscopic disease is, however, limited by systemic toxicity and multi-drug resistance. Immune surveillance is postulated to be operative in man. There is evidence, however, that patients with progressive tumour growth have failure of host defences both locally and systemically. Various possible defects and tumour escape mechanisms are discussed in the review. Immunotherapy and, in particular adoptive T cell therapy and DC therapy, show promise as putative tumour-specific therapy with clinical benefits. These techniques are undergoing development and evaluation in phase 1 clinical trials. Preliminary data suggest that the treatments are well tolerated. Unfortunately, there is limited evidence of significant and prolonged improvements in clinical outcome. Further developments of beneficial protocols (adjuvants, mode and frequency of vaccination etc) and multicentre studies of the use of immunotherapy in cancer are now required.

Head and Neck Neoplasms↗

PubMed2004

The role of gastrin in colorectal carcinogenesis.

Colorectal cancer is one of the leading causes of cancer-associated death in the United States and United Kingdom. In England and Wales, it is the second most common cancer in women and the third most common in men. Currently, treatment options for this debilitating disease are limited and surgical resection is the only curative treatment available. Despite rapid advances in surgery, as well as in adjuvant therapies such as radiotherapy and chemotherapy, there has been only a relatively modest improvement in mortality. The majority of colorectal cancers are epithelial-derived adenocarcinomas and arise from benign adenomas through the gain of mutations in key genes. Gastrin, an important polypeptide hormone, responsible for gastric acid secretion has been found to be involved in tumourigenesis in the gastrointestinal tract. When aberrantly expressed, the gastrin and gastrin/CCK-2 receptor genes can mediate powerful down stream events; the gastrin gene can impart anti-apoptotic properties while the gastrin/CCK-2 receptor can activate the transcription of a number of factors including ligands of the epidermal growth factor (EGF) receptor, the REG protein and matrix metalloproteinases (MMPs). In colonic tumourigenesis, gene expression of both gastrin and the gastrin/CCK-2 receptor is activated within epithelial cells at an early stage of the adenoma-carcinoma sequence. This review details the role played by gastrin in the adenoma-carcinoma sequence of colorectal carcinogenesis.

Adenocarcinoma↗

PubMed2003

Surgical sepsis: dysregulation of immune function and therapeutic implications.

Sepsis is defined clinically as the systemic inflammatory response of the host to the documented systemic infection. The pathophysiological disturbance involves both the innate and adaptive immune systems encompassing cellular immunity, humoral components and the complement system. Dendritic cells (antigen-presenting cells) are key cells involved in the regulation of the immune response in sepsis, in particular in activating T cells and especially inducing the production and secretion of specific cytokines. These are the main mediators in establishing prominent disturbances of inflammation in patients with sepsis. The clinical features of the sepsis syndrome may vary from minor clinical disturbances to severe multiple organ failure and death of the host. Appropriate therapeutic strategies for patients with sepsis utilise conventional therapy and new novel forms of treatment, which are showing promise for the future.

Cytokines↗

PubMed2003

Inflammatory bowel disease: dysfunction of GALT and gut bacterial flora (II).

The precise cause(s) of Crohn's disease and ulcerative colitis are unknown. From animal models and human studies it is well established that gut bacterial flora are essential for inducing the bowel inflammation. Animal models, when kept in a germ-free environment, do not develop colitis until the gut flora is reconstituted. It is not clear whether the bacterial antigens (Ags) from the normal flora or some other pathogenic bacterial Ags induce/propagate the inflammatory process in inflammatory bowel disease (IBD). Despite extensive research it has not been possible to identify any specific bacteria or virus as a credible cause of IBD. Recent understanding of quorum sensing molecules (QSMs) secreted by bacteria helps to explain the community behaviour in bacterial species. When QSMs reach a defined concentration, they activate bacterial proliferation and a number of virulence genes. Also, these molecules have been found to modulate the immune system to the advantage of the gut bacteria. They have not been well studied, however, in the gut. Inappropriate secretion of QSMs may alter the gut-associated lymphoid tissue (GALT) and, thereby, deregulate the immune tolerance normally present. Usefulness of probiotics and their immune modulating effects are being increasingly reported. Probiotics are also being used in the treatment of IBD. The interaction between the epithelial cells and the gut flora is very important as this is the first line of contact; this interaction may determine the induction of tolerance and mucosal integrity or immune activity, tissue inflammation and abnormal permeability. The latter is documented in patients with IBD and their healthy relatives. This may be an important factor in disruption of mucosal integrity and GALT dysfunction.

Animals↗

PubMed2003

Inflammatory bowel disease: dysfunction of GALT and gut bacterial flora (I).

Gut-associated lymphoid tissue (GALT) is the largest lymphoid organ in the body. This is not surprising considering the huge load of antigens (Ags) from food and commensal bacteria with which it interacts on a daily basis. Gut-associated lymphoid tissue has to recognise and allow the transfer of beneficial Ags whilst concurrently dealing with and successfully removing putative and overtly harmful Ags. This distinctive biological feature of GALT is believed to be crucial to good health. Deregulation or dysfunction of GALT is thought to predispose to inflammatory bowel diseases (IBD) such as ulcerative colitis and Crohn's disease. The exact mechanism(s) underlying the pathogenesis of IBD is (are) poorly understood and the immunological defects in GALT are poorly documented. Advances in immunology have highlighted the importance of dendritic cells (DCs), which are the key Ag presenting cells in tissues and lymphoid compartments. Their crucial role in GALT, in health and disease is discussed in this review. Interaction of DCs with T cells in the gut produces a subset of T lymphocytes, which have immunosuppressive function. Inappropriate Ag uptake and presentation to naïve T cells in mesenteric lymph nodes may lead to T cell tolerance in GALT. These various complex factors in the gut are discussed and their possible relevance to IBD evaluated.

Dendritic Cells↗

PubMed2003

Immune suppression and isolated severe head injury: a significant clinical problem.

In the developed world, trauma is the principal cause of death under the age of 40 and is the third largest overall killer. In the UK, approximately 25,000 people die each year as a result of major injury, 25% as a result of head injuries alone. Despite improved diagnosis and management, infection remains the commonest complication in those patients surviving the initial injury. Some 5% are reported to die as a result of septic complications. Prolonged periods of intensive care and respiratory support predispose to infective respiratory complications. These patients in the absence of significant systemic injury and, as a result of severe head injury, are unable to mount an effective immune response. This literature review examines the changes that have been reported to occur in the immune system following isolated severe head injury and explores the relationship these changes may have to the increased development of infective complications.

Antibody Formation↗

PubMed2002

Breast cancer in women aged 35 and under: prognosis and survival.

BACKGROUND: Breast cancer comprises 22% of all cancers occurring in females but only 2% of cases occur in women aged 35 years and less. The presentation, behaviour and prognosis of breast cancer in such women, when compared with older women, are unclear and conflicting results have been reported. This study has audited clinical and pathological features in patients aged 35 years and under with breast cancer. METHODS: One hundred and thirteen patients were identified. The details of clinical staging, local and distant disease recurrence and overall survival were obtained for all patients. Histological sections of tumours were examined for type, grade, size, presence of surrounding intraductal carcinoma, presence of vascular space invasion, lymph node involvement and oestrogen receptor (ER) status. RESULTS: Histological examination of the tumours revealed that 94% were invasive ductal carcinoma. In 73% of the cases the tumours were grade 3, 49% of patients who underwent axillary surgery had lymph node involvement and 20% of tumours expressed ERs. The overall 5-year survival was 64%. Predictors of a poorer survival (univariate analysis) were: increasing tumour size, absence of ERs, presence of lymphovascular space invasion, axillary lymph node involvement and detectable metastases at the initial presentation. Multivariate analysis revealed that only lymphovascular space invasion was an independent predictor of a poor survival. CONCLUSION: Breast cancer in young (< or = 35 years) women is biologically aggressive, compared with older women. Factors predicting survival and overall survival rates, however, were comparable with those previously reported for older women with breast cancer.

Adult↗

PubMed2001

Inhibition of the contraction of collagen gels by extracts from human dermis.

Extracts from the human dermis were prepared and evaluated with respect to their ability to influence fibroblasts to contract collagen gels in vitro. The extract which had the most inhibitory effect on fibroblasts to cause contraction of collagen gels was extract D. It also inhibited fibroblast growth. Inhibition of contraction was not simply related to fibroblast cell numbers and the data suggests a specific effect upon the ability of fibroblasts to cause contraction. Other extracts were without significant effect.

Cell Division↗

PubMed2001

What is achieved by mammographic surveillance after breast conservation treatment for breast cancer?

BACKGROUND: After breast conservation surgery for breast cancer, patients are followed up by regular clinical examination and mammography, at intervals which vary according to local practice. However, the optimum interval remains unclear with current guidelines suggesting mammography should be carried out every 1 to 2 years. This study has investigated this aspect and, in particular, whether mammography or clinical examination or both allowed an early detection of recurrence of the disease in the conserved breast. METHODS: A total of 695 patients who had undergone breast conservation surgery were identified from a database of prospectively recorded data during the period 1990 to 1995. Clinical examination and annual mammography were performed in accordance with local protocol. The results of clinical examination, mammography, and local recurrence rates were evaluated. RESULTS: A total of 2,181 mammograms were undertaken in the 695 patients studied. Local recurrence of disease in the conserved breast occurred in 21 patients (3%), at a mean follow-up of 3.5 years. The first identification of tumor recurrence was by clinical examination in 11 patients with local recurrence, and by the surveillance mammography in the other 10 patients with local recurrence. Overall, mammography detected the local recurrence in 13 of 20 (65%) patients who underwent this examination. In the other patients, the recurrence was detected on clinical examination only. In addition, in 52 patients, mammography was falsely positive, giving a false positive rate of 2.3%. Contralateral cancers in the opposite breast were detected in 2 patients. CONCLUSIONS: The detection of local disease after breast conservation surgery requires both clinical examination and mammography. In the context of our follow-up policy, in 52% of patients with local recurrence, this was first identified by clinical examination. Disease recurrence was identified in the other 48% of patients by mammographic surveillance. Overall, mammography will identify or confirm local recurrence in two thirds of women. However, in a small number of cases (2.3% in our series) mammography will give false positive results. New imaging modalities to assist in the diagnosis of local recurrence of disease after breast conservation surgery are required.

Adult↗

PubMed2001

Dendritic cells (I): Biological functions.

Dendritic cells (DCs) are potent antigen presenting cells (APCs) that possess the ability to stimulate naïve T cells. They comprise a system of leukocytes widely distributed in all tissues, especially in those that provide an environmental interface. DCs posses a heterogeneous haemopoietic lineage, in that subsets from different tissues have been shown to posses a differential morphology, phenotype and function. The ability to stimulate naïve T cell proliferation appears to be shared between these various DC subsets. It has been suggested that the so-called myeloid and lymphoid-derived subsets of DCs perform specific stimulatory or tolerogenic function, respectively. DCs are derived from bone marrow progenitors and circulate in the blood as immature precursors prior to migration into peripheral tissues. Within different tissues, DCs differentiate and become active in the taking up and processing of antigens (Ags), and their subsequent presentation on the cell surface linked to major histocompatibility (MHC) molecules. Upon appropriate stimulation, DCs undergo further maturation and migrate to secondary lymphoid tissues where they present Ag to T cells and induce an immune response. DCs are receiving increasing scientific and clinical interest due to their key role in anti-cancer host responses and potential use as biological adjuvants in tumour vaccines, as well as their involvement in the immunobiology of tolerance and autoimmunity.

Apoptosis↗

PubMed2001

Dendritic cells (II): Role and therapeutic implications in cancer.

The potential to harness the effectiveness and specificity of the immune system underlies the growing interest in cancer immunotherapy. One such approach uses bone marrow-derived dendritic cells (DCs), phenotypically distinct and very potent antigen-presenting cells, to present tumour-associated antigens (TAAgs) and, thereby, generate tumour-specific immunity. Support for this strategy comes from animal studies that have demonstrated that DCs, when loaded ex vivo with tumour Ags or pulsed with peptides and administered to cancer-bearing hosts, can elicit T cell-mediated cancer destruction. These observations have led to clinical trials designed to investigate the immunological and clinical effects of Ag-pulsed DCs administered as a therapeutic vaccine to patients with cancer. In the design and conduct of such trials, important considerations include Ag selection, methods for introducing TAAgs into MHC class I and II processing pathways, methods for isolating and activating DCs, and route of administration. Although current DC-based vaccination methods are cumbersome and complex, promising preliminary results from clinical trials in patients with malignant lymphoma, melanoma, and prostate cancer suggest that immuno-therapeutic strategies, that take advantage of the unique properties of DCs, may ultimately prove both efficacious and widely applicable treatment in patients with cancer.

Animals↗

PubMed2000

Serum cytokine profile in reflux nephropathy.

Cytokines are small regulatory peptides with diverse functions. They regulate the immune system and modulate the inflammatory response, both of which are implicated in vesico-ureteric reflux (VUR) and associated reflux nephropathy (RN). The cytokine profile in VUR and RN has yet to be fully investigated. Blood was obtained from three subject groups immediately after induction of anaesthesia: group A [subjects with VUR and established RN, (N=9)]; group B [VUR alone but no associated RN, (N=6)]; and group C [age- and sex-matched controls with no history of urinary sepsis, (N=14)]. Serum cytokine levels of tumour-necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), soluble TNF receptor-1 (sTNF-R1), and interleukin-8 (IL-8) were measured using standard ELISA technique. Serum levels of IL-6 were higher in group A subjects (1.798-4.638 pg/ml, median 3.253 pg/ml) than controls (1.531-2.078 pg/ml, median 1.798 pg/ml). There was no significant difference in levels in group B subjects (1.498-3. 048 pg/ml, median 1.948 pg/ml) and controls. These same relationships were observed for levels of TNF-alpha (group A: 8. 501-14.471 pg/ml, median 13.483 pg/ml; group B: 7.088-10.650 pg/ml, median 8.886 pg/ml; group C: 6.746-13.344 pg/ml, median 7.671 pg/ml) and sTNF-R1 (group A: 690.34-5780.74 pg/ml, median 1197.38 pg/ml; group B: 366.65-1401.62 pg/ml, median 592.82 pg/ml; C: 313.49-636.33 pg/ml, median 504.17 pg/ml). IL-8 was not significantly elevated in any of the study groups (A or B) compared with control group C (group A: 27.08-56.38 pg/ml, median 31.35 pg/ml; group B: 29.90-35. 87 pg/ml, median 31.35 pg/ml; group C: 25.05-30.22 pg/ml, median 29. 90 pg/ml). These results suggest there may be an immunological basis to RN.

Adolescent↗

PubMed2000

Distal proctocolitis and n-3 polyunsaturated fatty acids (n-3 PUFAs): the mucosal effect in situ.

It has been postulated that patients with ulcerative colitis (UC) have altered reactivity of gut-associated lymphoid tissue. In such cases there is intense infiltration of the mucosa with immune competent cells and associated tissue damage. We have shown previously that the dietary supplementation with the n-3 polyunsaturated fatty acids (n-3 PUFAs), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) results in significant systemic immune suppression. The aim of this study, therefore, was to evaluate the in situ effect of n-3 PUFAs on distal proctocolitis. Each patient received either fish oil extract (EPA 3.2 g, DHA 2.4 g) (n = 9) or sunflower oil (n = 9) daily in a double blind manner for six months. Monthly assessment included: (1) disease activity using clinical, sigmoidoscopic, and histological scores and (2) immunohistochemical analysis (immunoglobulins, CD profiles) of rectal biopsy specimens (before and after six months supplementation) using monoclonal antibodies and quantitative computer-assisted video image analysis. Prior to receiving supplementation, patients with proctocolitis (n = 18) showed significantly higher numbers of cells expressing CD3 (pan T cells) and HLA-DR and IgM containing cells compared with non-colitic controls (n = 8). Six months supplementation with n-3 PUFAs resulted in significant reduction in the number of cells expressing CD3 and HLA and the percentage of cells containing IgM. There was no significant change in the CD20 nor the percentage of IgG or IgA containing cells in either group of patients with procto-colitis. In patients receiving n-3 PUFA supplementation, there was improvement in the disease activity and histological scores, compared with pretreatment evaluation. This study has demonstrated both evidence of suppression of in situ immune reactivity and concurrent reduction in disease activity in patients with proctocolitis receiving n-3 PUFA supplementation. This may have important implication for therapy in patients with ulcerative colitis.

Animals↗

PubMed2000

Distal procto-colitis and n-3 polyunsaturated fatty acids: the mechanism(s) of natural cytotoxicity inhibition.

BACKGROUND: Altered natural killer (NK) and lymphokine-activated killer (LAK) cell activities have been reported with ulcerative colitis (UC). Previously, we have shown that in patients with UC, the n-3 polyunsaturated fatty acids (PUFAs), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), specifically inhibit natural cytotoxicity with clinical improvement in disease activity. The aim of this study therefore was to evaluate the possible mechanism(s) involved in this inhibition, and in particular the alteration of production of interleukin 2 (IL2) and the arachidonic acid metabolite leukotriene B4 (LTB4), both known to modulate NK cell activity. MATERIALS AND METHODS: Each patient with procto-colitis received either fish oil extract (EPA 3.2 g, DHA 2.4 g; n = 9) or placebo (n = 9) daily for 6 months. Monthly assessment included disease activity using clinical and sigmoidoscopic scores. Peripheral blood mononuclear (PBMN) cells were isolated and NK cell cytotoxic activity in vitro was measured. Monthly serum samples were analysed for LTB4, IL2 and soluble IL2 receptors (sIL2R). RESULTS: The n-3 PUFAs group had significantly reduced NK cell activity, compared with the placebo group (P < 0.05, Mann-Whitney U-test). In the n-3 PUFA group, incubation of PBMN cells for 72 h with recombinant interleukin 2 (rIL2) reversed the NK inhibition. In patients with active proctocolitis, serum levels of LTB4 correlated positively with NK cell cytotoxicity (r = 0.873, P < 0.05, Kendall's correlation coefficient). After six months of n-3 PUFAs supplementation, serum levels of LTB4 were undetectable with concurrent significant reduction in NK cell cytotoxic activity. The latter was associated with significant reduction of serum IL2 and sIL2R levels (P < 0.05). CONCLUSION: This study has demonstrated both evidence of suppression of immune reactivity and concurrent reduction in disease activity in patients with proctocolitis receiving n-3 PUFAs supplementation. This may have important implications for therapy in patients with UC.

Cytotoxicity, Immunologic↗