Can urinary exosomes act as treatment response markers in prostate cancer?

Background  

Recently, nanometer sized vesicles (termed exosomes) have been described as a component of urine. Such vesicles may be a useful non-invasive source of markers in renal disease. Their utility as a source of markers in urological cancer remains unstudied. Our aim in this study was to investigate the feasibility and value of analysing urinary exosomes in prostate cancer patients undergoing standard therapy.     

Can oral pathogens influence allergic disease?

The hygiene hypothesis contends that fewer opportunities for infections and microbial exposures have resulted in more widespread asthma and atopic disease. Consistent with that hypothesis, decreases in infectious oral diseases over the past half century have coincided with increases in the prevalence of asthma and other allergic diseases. This observation has led some researchers to speculate that exposures to oral bacteria, including pathogens associated with periodontal diseases, such as gingivitis and periodontitis, might play a protective role in the development of asthma and allergy. Colonization of the oral cavity with bacteria, including some species of periodontal pathogens, begins shortly after birth, and the detection of serum antibodies to oral pathogens in early childhood provides evidence of an early immune response to these bacteria. Current knowledge of the immune response to oral bacteria and the immunologic pathogenesis of periodontal diseases suggests biologically plausible mechanisms by which oral pathogens could influence the risk of allergic disease. However, studies investigating the association between oral pathogen exposures and allergic disease are few in number and limited by cross-sectional or case-control design, exclusion of young children, and use of surrogate measures of oral bacterial colonization. Additional studies, particularly well-designed case-control studies among very young children and prospective birth cohort?studies, are needed.     

Can treatment during primary HIV infection lead to control of disease without drugs?

Initiating antiretroviral treatment during PHI, particularly in the acute phase (before seroconversion), appears to interrupt the natural history of HIV infection in the host. Although all the parameters of such an interruption are not understood, what remains clear is that a condition can be induced where the host is better able to control viremia in the absence of therapy. Structured treatment interruptions, therapeutic vaccines, and other novel mechanisms may further enhance HIV-specific immunity and viral suppression. The duration of such effects, their outcome on survival, and how they apply to chronic infection are not known. However, just as the study of long-term nonprogressors has provided valuable information about host-virus interactions, so too may the study of induced host control of viremia lead to improved therapeutic approaches and perhaps one day a functional cure.     

Is continuous treatment with transforming growth factor-beta necessary to induce chondrogenic differentiation in mesenchymal stem cells?

This study was conducted to determine whether short-term administration of transforming growth factor (TGF)-beta would be as effective for inducing chondrogenesis in human mesenchymal stem cells (hMSCs) as continuous treatment. Four groups of hMSCs were cultured in a monolayer for 3 days followed by a pellet culture for 3 weeks under various conditions: group A, the control group, no growth factors treated; group B, 5 ng/ml of TGF-beta(2) was treated for 3 days in monolayer culture; group C, 5 ng/ml of TGF-beta(2) was treated for 3 days in a monolayer culture and the initial 3 days of pellet culture; group D, 5 ng/ml of TGF-beta(2) was treated for 3 days in a monolayer culture and the initial 10 days of pellet culture; group E, 5 ng/ml of TGF-beta(2) was continuously treated throughout the culture period. Glycosaminoglycan contents significantly increased in group E only. Real-time PCR indicated that expression of Sox-9, type II collagen, type II procollagen B and type X collagen increased with longer duration of TGF-beta(2) treatment. The histological findings showed that longer duration of TGF-beta(2) treatment led to significantly better quality of chondrogenesis. This study demonstrated that longer duration of TGF-beta treatment is necessary for effective chondrogenesis in hMSCs from bone marrow.     

Can p53 staining be used to identify patients with aggressive superficial bladder cancer?

Approximately 10% of patients with superficial bladder cancer (pTa/pT1) recur with life-threatening muscle-invasive disease. Identification of these patients has been a major goal of bladder cancer research. In 1994, it was suggested that p53 immunostaining could identify the cancers that would progress and it was proposed that tumours that stain for p53 should be treated aggressively with radiotherapy or cystectomy. Despite the hundreds of studies published since on the relationship between p53 and progression in superficial bladder cancer, the clinical utility of p53 immunostaining has not been resolved because of limitations concerning the numbers of patients and the length of follow-up. This study set out to overcome these limitations by using tissue from a large multicentre trial that recruited 502 patients with a median follow-up of 10 years. Each of 34 patients that had progressed with >/= pT2 disease or had distant metastases or had died from bladder cancer was compared with one or two matched controls. Sections were stained with a mouse monoclonal antibody to p53, pAb1801. In agreement with many of the earlier studies, p53 immunostaining had prognostic significance. The adjusted hazard ratio for time to progression for the pAb1801-positive versus negative group was 2.5, with 95% confidence intervals of 1.05-5.98 (p = 0.039). The other major risk factor that is associated with progression of superficial bladder cancer is pT1G3 disease. Of the 42 pT1G3 cancers, 14 (33%) progressed. The proportion of cancers with p53 staining that progressed was similar to the proportion of pT1G3 cancers that progressed, but neither the sensitivity nor the specificity of association of p53 staining with progression is sufficient to recommend cystectomy in individual patients.     

High prostate cancer mortality in Norway: influence of Cancer Registry information?

Norway has among the highest prostate cancer mortality rates in the world. The aim of the present project was to assess whether this can be explained by the unique routine procedure of information transfer from the Cancer Registry of Norway (CR) to the Norwegian Cause of Death Registry (COD Registry). Norwegian prostate cancer patients deceased during 1996 were identified (n=2012). The information basis of the official mortality statistics was reviewed by two physicians, who independently identified the underlying cause of death, primarily prostate cancer or not, supplemented by consensus of two other physicians. The coding was done in two steps; first without, then with CR information. Project physicians identified 1063 deaths from prostate cancer as compared to the official number of 1161, with discrepancy as to prostate cancer death in 126 deceased. Information from the CR increased the project's age-adjusted (world standard population) prostate cancer mortality rate by less than 1% (from 22.7 to 22.9 per 100,000). In conclusion, the high rates of prostate cancer mortality in Norway could not be explained by information transfer from the CR to the COD Registry.     

Does the microenvironment influence the cell types of origin for prostate cancer?

Despite several recent studies addressing the cells of origin for prostate cancer, there is still considerable discussion in the field regarding the most relevant target populations for transformation. Tissue regeneration studies have pointed to a basal cell origin for mouse and human prostate cancer. In contrast, genetically engineered mouse models demonstrate that cells within both the basal and luminal layers can initiate murine prostate cancer. Based on differences between these two approaches, we propose that further work should address the requirement for microenvironmental components such as immune or mesenchymal cells on epithelial cell types of origin for prostate cancer.     

Can Reed-Sternberg cells of classic Hodgkin's disease be considered B-cells?

During the last twenty years, the issue of the nature of Reed-Sternberg (RS) cells of Hodgkin's disease (HD) has been addressed by multiple methodological approaches. In recent times, a major insight into HD has been obtained through molecular studies of isolated cells which have proven the clonal nature of HD. In parallel to molecular investigations some novel biologic markers specifically associated with the different stages of mature B-cells have helped to define the cellular origin of HD. This review deals with histological features of HD and summarizes recent results from molecular and immunohistochemical studies focusing on the origin and the stage of differentiation of RS cells.     

How to assess disease activity in patients with chronic urticaria?

Background:  The current EAACI/GA²LEN/EDF guidelines recommend assessing disease activity in chronic urticaria (CU) by using an established and well-defined symptom score, i.e. the urticaria activity score (UAS), which combines daily wheal numbers and pruritus intensity. However, this UAS has never been formally tested for its suitability in assessing CU activity.
Aim:  To determine the UAS correlation with quality of life (QoL) in CU patients and to compare the UAS to other symptom scores.
Methods:  Chronic urticaria symptoms (wheals, erythema, angioedema, pruritus) were assessed on seven consecutive days in 111 CU patients for their numbers, duration, size, and/or intensity. Quality of life was assessed by using the Dermatology Life Quality Index. Both, urticaria activity and QoL were determined before and after a 3-week period, in which the patients followed a pseudoallergen-low diet.
Results:  Urticaria activity score values correlated positively, albeit weakly, with QoL impairment in CU patients ( r ² = 0.31, P  < 0.05). Also, changes in QoL following a pseudoallergen-low diet were reflected by the changes observed in the UAS ( r ² = 0.30, P  < 0.05). No significant differences were found comparing the QoL correlation of the UAS and other symptom scores combining up to four CU symptom qualities. Quality of life correlation with UAS values increased with the number of days the UAS was assessed and plateaued starting from the fourth consecutive day.
Conclusions:  Our findings back the current guideline recommendations to use the UAS for monitoring disease activity in CU patients. Urticaria activity score mean values of at least four consecutive days should be used.     

FGF23: Mediator of poor prognosis in a sizeable subgroup of patients with castration-resistant prostate cancer presenting with severe hypophosphatemia?

Castration-resistant prostate cancer (CRPC) is an advanced and incurable stage of the second most frequently diagnosed malignancy in men globally. Current treatment options improve survival modestly but eventually fail due to intrinsic or acquired therapeutic resistance. A hypothesis is presented wherein circulating levels of fibroblast growth factor 23 (FGF23), an endocrine member of the fibroblast growth factor family with phosphaturic properties, are proposed as a prognostic and predictive marker to identify CRPC patients with poor prognosis that are amenable to FGF23 antibody therapy (FGF23i) or treatment with fibroblast growth factor receptor inhibitors (FGFRi). With respect to the latter, FGF23 may also serve as a pharmacodynamic marker enabling individualized FGFRi dosing.     

Recurrence cancer stem cells – Made by cell fusion?

Within the past 10–15 years our knowledge about cancer and how cancer cells might originate has changed dramatically. It is now generally believed that a tumor has its origin in cancer stem cells (CSCs), which originated either from transformed tissue stem cells or transformed progenitor cells that have regained self-renewal activity. CSCs share several characteristics of normal stem cells, such as self-renewal capacity, slow cell cycle activity, differentiation capacity, possessing an enhanced resistance towards cytotoxic agents and radiation, as well as tissue restoration capacity. Due to the increased drug and radiation resistance and slow cell cycle activity concomitant with tumor initiation capacity it is generally assumed that recurrent cancers originate from first line therapy surviving CSCs. But how does the CSC hypothesis explain “oncogenic resistance”, which describes the phenomenon that most recurrent cancers are characterized by both an increased malignancy as well as resistance towards first line cancer therapy. To us, “oncogenic resistance” can not be simply attributed to the resistance properties of normal CSCs. If so, the recurring tumor should be treatable by first line therapy, which is mostly not the case. Thus, we conclude that “oncogenic resistance” demands a new type of tumor initiating cells, the so-called recurrence CSCs (rCSCs). This type of tumor initiating cell originates during first line therapy and is characterized by giving rise to first line therapy resistant and highly malignant progenies. Because several characteristics of “oncogenic resistance”, such as increased drug resistance, increased resistance to apoptosis and an enhanced malignancy have been linked to cell fusion we further conclude that rCSCs might originate from this cellular event. However, which cell types have to fuse with each other to ultimately give rise to rCSCs is not clear. In any case, tumor tissues, particularly those being destructed by first line therapy comprise of a variety of fusogenic cells including tumor cells and CSCs as well as recruited monocytes/macrophages and bone marrow-derived stem cells. The fusogenic properties of these cells concomitant with phenotypic heterogeneity, which is also a property of cell fusion, will then lead to the origin of rCSCs. In accordance with Darwinian evolution only those cells will survive that can resist best to the selection pressure first line therapy.