Myeloid derived suppressor cells in breast cancer: A novel therapeutic target?

The relationship of the immune system and tumour cells is complex; although recognised that the immune system can protect the host against tumour development, the immune system also facilitates tumour progression through immune suppression. Pro-inflammatory mediators associated with chronic inflammation are responsible for the expansion and activation of myeloid derived suppressor cells (MDSCs); a heterogeneous group of cells that originates from myeloid progenitor cells but does not complete the final stages of differentiation. A causal relationship between chronic inflammation and tumour progression relies on the accumulation and maintenance of MDSCs as its linchpin; responsible for immunosuppression through the down-regulation of anti-tumour responses. MDSCs cause immunosuppression through a number of mechanisms; inhibiting the proliferation of CD4⁺ and CD8⁺ T cells, blocking natural killer cell activation and limiting dendritic cell maturation and function. As well as using various mechanisms to inhibit adaptive and immune responses, MDSCs also have non-immunological functions that aid tumour spread; including directly promoting tumour proliferation and metastasis by having an important role in tumour angiogenesis, secretion of matrix metalloproteinases and induction of epithelial-mesenchymal transition. Breast cancer is the most common cancer among women in the United Kingdom with 44540 new cases of invasive carcinoma in 2013 and results in the second highest cancer mortality rate in women, with 11600 deaths in 2012. Considering this, the need for novel therapeutic interventions is higher than ever. This review summarises the rationale for the targeting of MDSCs in breast cancer as a realistic avenue to increase survival from breast cancer.     

Glia-related pathomechanisms in Alzheimer's disease: a therapeutic target?

Reactive glial cell properties could contribute to pathomechanisms underlying Alzheimer's disease by favoring oxidative neuronal damage and beta-amyloid toxicity. A critical step is apparently reached when pathological glia activation is no longer restricted to microglia and includes astrocytes. By giving up their differentiated state, astrocytes may lose their physiological negative feed-back control on microglial NO production and even contribute to neurotoxic peroxynitrate formation. Another consequence is the impairment of the astrocyte-maintained extracellular ion homeostasis favoring excitotoxic damage. By the production of apolipoprotein-E, triggered by the microglial cytokine interleukine-1beta, reactive astrocytes could promote the transformation of beta-amyloid into the toxic form. A pharmacologically reinforced cAMP signaling in rat glial cell cultures depressed oxygen radical formation in microglia and their release of TNF-alpha and interleukine-1beta, feed-forward signals which mediate oxidative damage and secondary astrocyte activation. Cyclic AMP also favored differentiation and expression of a mature ion channel pattern in astrocytes improving their glutamate buffering. A deficient cholinergic signaling that increases the risk of pathological APP processing was compensated by an adenosine-mediated reinforcement of the second messenger calcium. A combination therapy with acetylcholine-esterase inhibitors together with adenosine raising pharmaca, therefore, may be used to treat cholinergic deficiency in Alzheimer's disease.     

Inhibition of return in cue–target and target–target tasks

Inhibition of return (IOR), the term given for the slowing of a response to a target that appeared at the same location as a previously presented stimulus, has been studied with both target–target (TT; participants respond to each successive event) and cue–target (CT; participants only respond to the second of two events) tasks. Although both tasks have been used to examine the processes and characteristics of IOR, few studies have been conducted to understand if there are any differences in the processes that underlie the IOR that results from ignoring (CT paradigm) or responding to (TT paradigm) the first stimulus. The purpose of the present study was to examine the notion that IOR found in TT tasks represents “true” IOR whereas IOR found in CT tasks consist of both “true” IOR and response inhibition (Coward et al. in Exp Brain Res 155:124–128, 2004). Consistent with the pattern of effects found by Coward et al. (Exp Brain Res 155:124–128, 2004), IOR was larger in the CT task than in the TT task when a single detection response was required (Experiment 1). However, when participants completed one of two spatially-directed responses (rapid aiming movement to the location of the target stimulus), IOR effects from the CT and TT tasks were equal in magnitude (Experiment 2). Rather than CT tasks having an additional response inhibition component, these results suggest that TT tasks may show less of an inhibitory effect because of a facilitatory response repetition effect.     

The role of endothelial dysfunction in the pathogenesis of impaired diabetic wound healing: A novel therapeutic target?

The global burden of diabetes is attributed to its multiple associated complications including impaired wound healing which can ultimately result in amputation. Peripheral vascular disease, infection, neuropathy and abnormal local cellular and cytokine activity are some of the traditionally cited pathological instigators of defective diabetic wound repair. Despite intensive research and subsequent advances in diabetic wound care technology a single treatment with measurable clinical impact has yet to be determined. The phenomenon of endothelial dysfunction as seen in atherosclerosis and recently identified as a characteristic of diabetic vasculature may contribute to impaired cutaneous healing in this group. Indicators of endothelial dysfunction have been demonstrated in diabetic wounds by a number of investigators. Successful results are being obtained with modifiers of endothelial function in the management of cardiovascular disease. We hypothesise that endothelial dysfunction plays a substantial contributory role in the pathogenesis of wound healing impairment of diabetes and holds potential as a target for therapeutic intervention.     

The potential role of microRNA-146 in Alzheimer's disease: biomarker or therapeutic target?

Recently, there have been increasing evidences that microRNA-146 (miR-146) is related to up-regulated immune and inflammatory signaling through its target genes, such as IRAK1 and TRAF6. Additionally, abundant data continue to support the hypothesis that progressive up-regulation of inflammatory gene expression and elevated inflammatory signaling facilitate the development and progression of Alzheimer’s disease (AD). This review focuses on the recent findings regarding the role of miR-146 in modulating immune response and its subsequent effects in the pathogenesis of AD.     

Polyomavirus BK – A potential new therapeutic target for painful bladder syndrome/interstitial cystitis?

Aims

To investigate the role of urinary BK polyoma virus (BKPyV) in the pathophysiology and prognosis of patients with painful bladder syndrome/interstitial cystitis (PBS/IC).

Methods

Urine samples were collected from 15 patients with PBS/IC and 8 control patients (with urolithiasis, overactive bladder and benign prostatic hyperplasia). BKPyV titres were quantitatively determined using real time PCR. Fisher’s exact test was used to compare virus titre levels between the two groups. The PBS/IC patients subsequently underwent cystoscopy, hydrodistension and bladder biopsy. Finally, a chart review was performed in order to correlate PBS/IC subtype and treatment outcomes with BKPyV status.

Results

Positive BKPyV titres were found in 11 out of 15 PBS/IC patients but none of the controls. Cystoscopy was performed in 13 of the 15 PBS/IC patients (in 2 BKPyV positive patients, cystoscopy was not performed). Bladder ulceration and glomerulations were observed in all 9 BKPyV positive PBS/IC patients but only 1 out of 4 BKPyV negative patients. None of the non-ulcerative PBS/IC patients had BKPyV positive urine. Viral titres were not predictive of the clinical course however, 3 patients with the highest viral titres eventually underwent cystectomy.

Conclusions

We identified BKPyV in the urine of virtually all our patients with ulcerative PBS/IC. This finding suggests there may be a pathophysiological association between the virus and the haemorrhagic manifestations of PBS/IC. Classifying PBS/IC patients into BKPyV positive or negative groups may prove useful in future research on markers of disease prognosis and the subtypes of PBS/IC. We believe that BKPyV may therefore have a role as a potential therapeutic target in PBS/IC.     

Is HMGB1 a new indirect marker for revealing fibrosis in chronic hepatitis and a new therapeutic target in treatment?

In chronic hepatitis B virus (HBV) infection, inflammation-associated cytokines including proinflammatory cytokines are involved in the development and progression of liver fibrosis. The liver is a source of many cytokines that may influence liver function. High-mobility group box 1 (HMGB1) was identified as an inflammatory cytokine. HMGB1 is present in nuclei of all mammalian cells and is released both through active secretion from various cells and by passive release from necrotic cells. Here we explore the relationship between HMGB1 plasma levels and liver fibrosis. HMGB1 serum levels, HBV-DNA, and ALT values were significantly higher in patients with chronic HBV than in controls. In addition, HMGB1 serum levels were significantly higher in patients with low fibrosis (fibrosis score 1-2) compared to those with high fibrosis (fibrosis score 3-4). In the present study, we have shown that HMGB1 is a noninvasive, repeatable, and convenient marker for distinguishing advanced fibrosis from low fibrosis in chronic HBV patients. We believe that the inhibition of HMGB1 may reduce inflammation, apoptosis, and fibrosis, and may stop the progression of chronic liver disease. Furthermore, we are of the opinion that fibrotic progression in chronic liver patients may be prevented by the inhibition of HMGB1, and that this substance can be a new means of following chronic HBV treatment.     

Angiopoietin-like protein 4: A therapeutic target for triglycerides and coronary disease?

The angiopoietin-like proteins are a family of proteins that share structural similarities to the angiopoietins. These proteins have been described to play a key role in the regulation of a myriad of physiologic processes, including serving as essential modulators of lipid and glucose metabolism. Angiopoietin-like protein 4 (ANGPTL4) is a key regulator of lipoprotein lipase, and its modulation has been shown to significantly impact the body's processing and distribution of triglycerides and cholesterol. Although more research remains to elucidate the full range of mechanisms through which ANGPTL4 affects triglyceride and cholesterol homeostasis, current research has associated decreased ANGPTL4 function with a beneficial effect on lipid parameters and overall cardiovascular disease risk, opening the possibility of ANGPTL4 as a new therapeutic target for the treatment of cardiovascular disease.     

Risk factor–gene interaction in carotid atherosclerosis: effect of gene polymorphisms of renin-angiotensin system

The risk factor–gene interaction in carotid atherosclerosis was investigated in 205 community-dwelling healthy subjects aged 50 years or more in Japan. The intima–media thickness (IMT) of the common carotid artery was evaluated by ultrasonography with a 7.5-MHz probe. Gene polymorphisms were determined for each subject with angiotensin-converting enzyme (ACE) insertion/deletion (I/D), angiotensinogen (AGT) M235T, angiotensin II type 1 receptor (AT1R) A1166C, and apolipoprotein E (apoE) genotypes. There was no genotype-specific difference in carotid IMT among any genes examined. Combinations of genotypes did not increase carotid IMT compared with subjects without these genotypes. In the total population, multiple regression analysis showed that age, systolic blood pressure (SBP), sex, and body mass index (BMI) were significantly associated with carotid IMT. However, the association between risk factors and IMT was genotype-specific. Age was significantly associated with IMT in ACE D carriers, but not in subjects with the ACE II genotype. Analysis of covariance adjusted with other risk factors showed that the age-dependent change in IMT was significantly different between subjects with the ACE II genotype and the ACE D carriers (F[1.196] = 4.97; P = 0.027). Similarly, the regression of IMT on SBP was significantly different between AGT TT and AGT MT + MM (F[1.196] = 7.20; P = 0.0079). The regression of IMT on BMI was also significantly different between apo E4 carriers and noncarriers (F[1.196] = 6.78; P = 0.0099). Furthermore, general linear model analysis with risk factors, genotype, and risk factor-genotype interactions revealed that the age^*ACE genotype interaction, the SBP^*AGT genotype interaction, and the BMI^*apoE genotype interaction were significantly associated with IMT. These findings further support the role of risk factor-gene interaction in carotid atherosclerosis. Received: January 5, 2001 / Accepted: February 5, 2001     

CNTF: a target therapeutic for obesity-related metabolic disease?

Obesity and type 2 diabetes are the most prevalent metabolic diseases in the western world. Alarmingly, the cluster of pathologies characteristic of obesity-induced disease have started to emerge in children, a phenomenon that up until a decade ago was inconceivable. Hence, the development of new strategies to treat 'metabolic disease' is most warranted. Growing evidence suggests that during type 2 diabetes, a state of chronic low-grade inflammation exists in metabolically active tissues such as the liver, adipose tissue and skeletal muscle. This inflammation is often secondary to lipid accumulation in insulin-responsive tissues. Recent studies have focused on the therapeutic potential of ciliary neurotrophic factor (CNTF). CNTF is a pluripotent neurocytokine and, has shown promise as a potential anti-obesogenic therapy. CNTF acts both centrally and peripherally, mimics the biological actions of leptin while overcoming "leptin resistance", remains effective even after termination of therapy if administered centrally, and appears to reduce inflammatory signaling cascades associated with lipid accumulation in liver and skeletal muscle. The advantages and disadvantages of CNTF as a therapeutic strategy to alleviate obesity-associated diseases will be highlighted in this review.     

New clinical and experimental approaches for studying tumor dormancy: does tumor dormancy offer a therapeutic target?

Tumor dormancy is a significant clinical problem. Primary treatment of a cancer may be apparently successful, and yet the tumor may recur either locally or as distant metastases years or even decades later. The ability to predict which patients are likely to develop recurrences is imprecise, relying on probabilities of recurrence based on features of the primary cancer. This uncertainty presents clinical challenges regarding who to treat and how, in order to prevent recurrence after periods of dormancy. Recent clinical trials in breast cancer support the idea that some patients may harbor tumor cells that are capable of forming late-developing metastases years after removal of the primary tumor, and that these dormant cancer cells may in some cases be effectively treated with long-term therapy. Advances in experimental studies of tumor dormancy are shedding light on the nature of dormancy, and are providing both new technologies and conceptual approaches for studying tumor dormancy. A better understanding of mechanisms responsible for tumor dormancy and recurrence will be important for improving care of patients at risk for late-developing metastases.     

Neurogenesis in the amygdala: A new etiologic hypothesis of autism?

Neurogenesis studies had an increased development after BrdU (5-bromo-3'-deoxyuridine), a marker of cell proliferation. Today, several studies have showed the relevance of neurogenesis in the hippocampal formation. Notwithstanding, other brains areas have been described presenting neurogenesis, including the amygdala. This key structure is a complex cerebral region which has been associated with social behaviors and the emotional significance of the daily experiences. Several studies have associated the amygdala to the autism, a severe neurodevelopmental disorder. In this paper, we discuss the hypothesis of neurogenesis in the amygdala as a contributing cause of autism. The social skills require competent new neuronal connections, including efficient plasticity synaptic rearranging. Interestingly, emotional context cannot be imprinting in mature neurons in the presence of GABA, a neurotransmitter release during new environments experiences. However, it is known that new neurons are not well responsive to GABA stimulation, allowing the long-term potentiation necessary for the learning process. Based on these evidence it is tantalizing to hypothesize that the sociability impairment seen in some individuals with autism may partly be assigned to impaired regulation of the GABAergic system and to the impact of this impairment on the adequate functioning of the amygdala and on its capacity to store new experiences and to modulate the plasticity of the corticostriatal connections.     

Can NK cells be a therapeutic target in human diseases?

Our current knowledge of NK-cell recognition and effector function suggests that it will be possible to design various new NK-cell-based immunotherapies against human cancer. The application of NK cells is already showing promise using HLA-mismatched haematopoietic stem cell transplantation for treatment of haematological malignancies. A better understanding of NK-cell heterogeneity and function will only broaden the applications for human cancer. Here we review the key developments that will propel this field.     

Breathing during cardiac arrest following exercise: A new function of the respiratory system?

We have found in four sheep that, following a muscular exercise, minute ventilation is maintained for 34-131 s during a cardiac arrest (CA), at a magnitude (from 28.2 and 54.7 l min(-1)) similar to the level of ventilation (and thus proportional to the metabolic rate) preceding the period of asystole. Breathing was maintained despite the lack of pulmonary blood flow and the cessation of the muscle contractions, leading to a dramatic reduction in alveolar FCO(2) (1.9 ± 1%). Secondly, swings in arterial blood pressure (ABP) were observed (pulse pressure of 31 ± 3 Torr) in phase with breathing movements in place of the cardiac activity. This "protective" response, deprived from any role in blood gas homeostasis, as circulation is virtually abolished, is not predictable from the traditional respiratory control feedback systems thought to be involved in exercise. We are presenting the view that this response, dissociated from the pulmonary gas exchanges, is the expression of a rudimentary defense mechanism aimed at limiting the consequences of an acute failure of the cardiac pump by the thoraco-abdominal pump.