The REAL process - a process for recycling sludge from water works

In order to produce drinking water, coagulants - such as aluminium salts - are widely used for precipitation and separation of impurities from raw water. The residual from the process is sludge, which presents a disposal problem. The REAL process is a method for recycling the aluminium from the sludge. In a first step, the aluminium hydroxide is dissolved in sulphuric acid. In a second step, an ultra filtration will separate all suspended matter and large molecules, leaving a concentrate of 15-20% dry solids. The permeate will contain the trivalent aluminium ions together with 30-50% of the organic contaminants. In a third step, by concentrating the permeate in a nano filter, the concentration of aluminium will be high enough to, in a fourth step, be precipitated with potassium sulphate to form a pure crystal: potassium aluminium sulphate. The potassium aluminium sulphate is comparable to standard aluminium sulphate. The process will give a residual in form of a concentrate from the ultra filtration, representing a few per cent of the incoming volume. This paper presents the results from a long time pilot-scale continuous test run at Vasteras water works in Sweden, as well as calculations of costs for full-scale operations

A Novel Automated Platform for Quantifying the Extent of Skeletal Tumour Involvement in Prostate Cancer Patients Using the Bone Scan Index

Prostate cancer (PCa) is one of the most common diseases in the world. PCa can primarily disseminate to the bone, causing bone metastases, which in turn can lead to death. It is important to diagnose bone metastases as soon as possible in order to treat the disease. Bone metastases are diagnosed commonly by bone scan imaging. However, interpretation of bone scan images is not always an easy task for physicians. One way of minimising the risk of misinterpretation is quantitative analysis of bone scan images in order to ascertain whether they show any metastatic lesions, and if so, to what extent. Quantification of the bone scan, i.e. the bone scan index (BSI) method, could be used for prognostication of survival, or to follow up the effect of treatment. The aim of the thesis was to develop and validate a fully automated method for the quantification of skeletal images in patients with prostate cancer based on the BSI method. This thesis is based on four papers. In paper 1, "A Novel Automated Platform for Quantifying the Extent of Skeletal Tumour Involvement in Prostate Cancer Patients Using the Bone Scan Index", we developed an automated BSI-quantification method, used it in a training group of 795 patients, compared it to a manual method and assessed the prognostic value of BSI in an evaluating group of 384 patients. The automated method showed a good correlation (r=80%) with the manual method, and BSI was strongly associated with prostate cancer death. In paper 2, "Bone Scan Index: a prognostic imaging biomarker for high-risk prostate cancer patients receiving primary hormonal therapy”, we found that BSI included prognostic information in addition to other clinical parameters such as “prostate-specific antigens”. Patients with BSI5. In paper 3, “Progression of Bone Metastases in Patients with Prostate Cancer - Automated Detection of New Lesions and Calculation of Bone Scan Index”, we further develop the automatic method to find new metastases using a training group of 266 patients. The method evaluated 31 patients who received chemotherapy. Patients with an increase in BSI during treatment had a lower two-year survival rate (18%) than those with a decrease in BSI (57%). In the final paper, “Assessment of baseline and longitudinal bone scan index measures in the context of a randomised placebo-controlled trial of tasquinimod in men with metastatic castration-resistant prostate cancer (mCRPC)”, we retrospectively calculated BSI at baseline and upon treatment in 85 patients from a clinical trial. We found that BSI and BSI change on-treatment were associated with survival. BSI correlated with known biomarkers of survival, but adds independent prognostic information. In conclusion, BSI calculated using an automated method contains prognostic information and can be used to evaluate treatment effects

αvβ8 integrin-expression by BATF3-dependent dendritic cells facilitates early IgA responses to Rotavirus

International audienceSecretory intestinal IgA can protect from re-infection with rotavirus (RV), but very little is known about the mechanisms that induce IgA production during intestinal virus infections. Classical dendritic cells (cDCs) in the intestine can facilitate both T cell-dependent and -independent secretory IgA. Here, we show that BATF3-dependent cDC1, but not cDC2, are critical for the optimal induction of RV-specific IgA responses in the mesenteric lymph nodes. This depends on the selective expression of the TGF beta-activating integrin alpha v beta 8 by cDC1. In contrast, alpha v beta 8 on cDC1 is dispensible for steady state immune homeostasis. Given that cDC2 are crucial in driving IgA during steady state but are dispensable for RV-specific IgA responses, we propose that the capacity of DC subsets to induce intestinal IgA responses reflects the context, as opposed to an intrinsic property of individual DC subsets

PSA-Targeted Alpha-, Beta-, and Positron-emitting immunotheranostics in murine prostate cancer models and nonhuman primates

Purpose: Most patients with prostate cancer treated with androgen receptor (AR) signaling inhibitors develop therapeutic resistance due to restoration of AR functionality. Thus, there is a critical need for novel treatment approaches. Here we investigate the theranostic potential of hu5A10, a humanized mAb specifically targeting free PSA (KLK3). Experimental Design: LNCaP-AR (LNCaP with overexpression of wildtype AR) xenografts (NSG mice) and KLK3-Hi- Myc transgenic mice were imaged with 89Zr- or treated with 90Y- or 225Ac-labeled hu5A10; biodistribution and subcellular localization were analyzed by gamma counting, PET, autoradiography, and microscopy. Therapeutic efficacy of [225Ac]hu5A10 and [90Y]hu5A10 in LNCaP-AR tumors was assessed by tumor volume measurements, time to nadir (TTN), time to progression (TTP), and survival. Pharmacokinetics of [89Zr]hu5A10 in nonhuman primates (NHP) were determined using PET. Results: Biodistribution of radiolabeled hu5A10 constructs was comparable in different mouse models. Specific tumor uptake increased over time and correlated with PSA expression. Treatment with [90Y]/[225Ac]hu5A10 effectively reduced tumor burden and prolonged survival (P ≤ 0.0054). Effects of [90Y]hu5A10 were more immediate than [225Ac]hu5A10 (TTN, P < 0.0001) but less sustained (TTP, P < 0.0001). Complete responses were observed in 7 of 18 [225Ac]hu5A10 and 1 of 9 mice [90Y]hu5A10. Pharmacokinetics of [89Zr]hu5A10 were consistent between NHPs and comparable with those in mice. [89Zr]hu5A10-PET visualized the NHP-prostate over the 2-week observation period. Conclusions: We present a complete preclinical evaluation of radiolabeled hu5A10 in mouse prostate cancer models and NHPs, and establish hu5A10 as a new theranostic agent that allows highly specific and effective downstream targeting of AR in PSAexpressing tissue. Our data support the clinical translation of radiolabeled hu5A10 for treating prostate cancer

Internalization of secreted antigen-targeted antibodies by the neonatal Fc receptor for precision imaging of the androgen receptor axis

Targeting the androgen receptor (AR) pathway prolongs survival in patients with prostate cancer, but resistance rapidly develops. Understanding this resistance is confounded by a lack of noninvasive means to assess AR activity in vivo. We report intracellular accumulation of a secreted antigen-targeted antibody (SATA) that can be used to characterize disease, guide therapy, and monitor response. AR-regulated human kallikrein-related peptidase 2 (free hK2) is a prostate tissue-specific antigen produced in prostate cancer and androgen-stimulated breast cancer cells. Fluorescent and radio conjugates of 11B6, an antibody targeting free hK2, are internalized and noninvasively report AR pathway activity in metastatic and genetically engineered models of cancer development and treatment. Uptake is mediated by a mechanism involving the neonatal Fc receptor. Humanized 11B6, which has undergone toxicological tests in nonhuman primates, has the potential to improve patient management in these cancers. Furthermore, cellspecific SATA uptake may have a broader use for molecularly guided diagnosis and therapy in other cancers

Prostate kallikrein markers in diagnosis, risk stratification and prognosis.

The kallikrein, prostate-specific antigen (PSA), is one of the world's most frequently used disease biomarkers. After almost two decades of research and clinical experience, the diagnostic and monitoring limitations of PSA are beginning to be understood. Most physicians are aware of PSA's low specificity for cancer among older men with benign prostatic conditions; fewer are aware of recent data, which show that a prior negative biopsy or a prior PSA value below the threshold for biopsy might compromise the predictive accuracy of PSA even further. Furthermore, a subtle increase in serum PSA level during early middle age is strongly correlated with clinically important prostate cancer. We review current and past reports on the prostate kallikreins PSA and hK2 in relation to pathology and epidemiology

N-acetyltransferase 2 phenotype, occupation, and bladder cancer risk: results from the EPIC cohort.

BACKGROUND: An association between N-acetyltransferase 2 (NAT2) slow acetylation and bladder cancer has been consistently observed in epidemiologic studies. However, evidence has been mainly derived from case-control studies and was sparse from cohort studies. We evaluated the association between NAT2 slow acetylation and bladder cancer in a case-control study nested in the European Prospective Investigation into Cancer and Nutrition. METHODS: Exposure to aromatic amines and polycyclic aromatic hydrocarbons (PAH) could be assessed for 754 cases and 833 controls for whom occupational information was documented. A semiquantitative job-exposure matrix was applied to at-risk occupations to estimate the exposure as low, medium, or high based on tertiles of the distribution of the exposure score in controls. Using a comprehensive genotyping, NAT2 acetylation status could be categorized from 6-single-nucleotide polymorphism genotypes as slow or fast in 607 cases and 695 controls with DNA from archived blood samples. RESULTS: Occupational exposure to aromatic amines and PAH was associated with an increased bladder cancer risk [upper tertile of the distribution of the exposure score: OR = 1.37; 95% confidence interval (CI), 1.02-1.84, and OR = 1.50; 95% CI, 1.09-2.05, respectively]. NAT2 slow acetylation did not modify these risk estimates and was not itself associated with bladder cancer risk (OR = 1.02; 95% CI, 0.81-1.29). CONCLUSIONS: These findings confirm established or suspected occupational risk factors but not the anticipated role of NAT2 slow acetylation in bladder cancer. No interaction was detected between NAT2 and any exposure of interest, including smoking. IMPACT: Genetic testing for NAT2 would be inappropriate in occupational settings

Smoking and the risk of prostate cancer in the European Prospective Investigation into Cancer and Nutrition

Background: Smoking is not associated with prostate cancer incidence in most studies, but associations between smoking and fatal prostate cancer have been reported. Methods: During 1992 and 2000, lifestyle information was assessed via questionnaires and personal interview in a cohort of 145112 European men. Until 2009, 4623 incident cases of prostate cancer were identified, including 1517 cases of low-grade, 396 cases of high grade, 1516 cases of localised, 808 cases of advanced disease, and 432 fatal cases. Multivariable Cox proportional hazards regression models were used to examine the association of smoking status, smoking intensity, and smoking duration with the risk of incident and fatal prostate cancer. Results: Compared with never smokers, current smokers had a reduced risk of prostate cancer (RR = 0.90, 95% CI: 0.83-0.97), which was statistically significant for localised and low-grade disease, but not for advanced or high-grade disease. In contrast, heavy smokers (25+ cigarettes per day) and men who had smoked for a long time (40+ years) had a higher risk of prostate cancer death (RR = 1.81, 95% CI: 1.11-2.93; RR = 1.38, 95% CI: 1.01-1.87, respectively). Conclusion: The observation of an increased prostate cancer mortality among heavy smokers confirms the results of previous prospective studies