European Code against Cancer, 4th Edition: Cancer screening

In order to update the previous version of the European Code against Cancer and formulate evidence-based recommendations, a systematic search of the literature was performed according to the methodology agreed by the Code Working Groups. Based on the review, the 4th edition of the European Code against Cancer recommends: “Take part in organized cancer screening programmes for: • Bowel cancer (men and women)• Breast cancer (women)• Cervical cancer (women).”Organized screening programs are preferable because they provide better conditions to ensure that the Guidelines for Quality Assurance in Screening are followed in order to achieve the greatest benefit with the least harm. Screening is recommended only for those cancers where a demonstrated life-saving effect substantially outweighs the potential harm of examining very large numbers of people who may otherwise never have, or suffer from, these cancers, and when an adequate quality of the screening is achieved. EU citizens are recommended to participate in cancer screening each time an invitation from the national or regional screening program is received and after having read the information materials provided and carefully considered the potential benefits and harms of screening. Screening programs in the European Union vary with respect to the age groups invited and to the interval between invitations, depending on each country's cancer burden, local resources, and the type of screening test used For colorectal cancer, most programs in the EU invite men and women starting at the age of 50–60 years, and from then on every 2 years if the screening test is the guaiac-based fecal occult blood test or fecal immunochemical test, or every 10 years or more if the screening test is flexible sigmoidoscopy or total colonoscopy. Most programs continue sending invitations to screening up to the age of 70–75 years. For breast cancer, most programs in the EU invite women starting at the age of 50 years, and not before the age of 40 years, and from then on every 2 years until the age of 70–75 years. For cervical cancer, if cytology (Pap) testing is used for screening, most programs in the EU invite women starting at the age of 25–30 years and from then on every 3 or 5 years. If human papillomavirus testing is used for screening, most women are invited starting at the age of 35 years (usually not before age 30 years) and from then on every 5 years or more. Irrespective of the test used, women continue participating in screening until the age of 60 or 65 years, and continue beyond this age unless the most recent test results are normal

Does the Letter Matter (and for Everyone)? Quasi-Experimental Evidence on the Effects of Home Invitation on Mammography Uptake

We exploit regional variation in the availability of breast cancer screening policies and variations in age eligibility criteria across European regions to estimate the causal effect of home invitation on mammography uptake. We link administrative public data about regional breast cancer screening policies from various sources to individual Survey of Health Ageing and Retirement in Europe (SHARE) data. We find that home invitation increases mammography uptakes by almost 20 percentage points. At the same time, we find that home invitation reduces education-related inequalities but increases gradient in the use related to cognitive functions. In addition, significant effects on mammography use are found only when at least 50 per cent of the population is reached by the home invitation. Our results suggest that an exogenous informational shock affects preventive decisions especially among less informed individuals but the effectiveness of invitation is strongly reduced for women who are less able to process information.In diesem Papier nutzen wir regionale Unterschiede im Zugang zu Brustkrebs-Screening-Programmen sowie regionale Unterschiede in den altersspezifischen Teilnahmebedingungen, um den kausalen Effekt von schriftlichen Einladungen auf die Teilnahme an Mammographie-Screening-Programmen zu untersuchen. Hierzu werden administrative regionale Daten zu Brustkrebs-Screening-Programmen herangezogen und mit Individualdaten des Survey of Health Ageing and Retirement (SHARE) verknüpft. Wir finden heraus, dass die Einladung zum Screening die Teilnahme am Screening um fast 20 Prozentpunkte erhöht. Gleichzeitig reduziert die Einladung zum Screening bildungsbezogene Ungleichheiten in der Inanspruchnahme, jedoch erhöht sie kognitiv bezogene Ungleichheiten. Signifikante Effekte auf die Mammographieteilnahme werden nur gefunden, wenn mindestens 50 Prozent der Bevölkerung eine Einladung erhält. Unsere Ergebnisse lassen schlussfolgern, dass ein durch die schriftliche Einladung ausgelöster exogener Informationsschock einen starken Einfluss auf Präventionsentscheidungen hat. Diese Schlussfolgerung gilt insbesondere für weniger informierte Personen. Demgegenüber ist die Einladung zum Screening nicht so effektiv, wenn die Frauen weniger in der Lage sind Informationen zu verarbeiten

A novel small molecule that kills a subset of MLL-rearranged leukemia cells by inducing mitochondrial dysfunction

Survival rates for pediatric patients suffering from mixed lineage leukemia (MLL)-rearranged leukemia remain below 50% and more targeted, less toxic therapies are urgently needed. A screening method optimized to discover cytotoxic compounds selective for MLL-rearranged leukemia identified CCI-006 as a novel inhibitor of MLL-rearranged and CALM-AF10 translocated leukemias that share common leukemogenic pathways. CCI-006 inhibited mitochondrial respiration and induced mitochondrial membrane depolarization and apoptosis in a subset (7/11, 64%) of MLL-rearranged leukemia cell lines within a few hours of treatment. The unresponsive MLL-rearranged leukemia cells did not undergo mitochondrial membrane depolarization or apoptosis despite a similar attenuation of mitochondrial respiration by the compound. In comparison to the sensitive cells, the unresponsive MLL-rearranged leukemia cells were characterized by a more glycolytic metabolic phenotype, exemplified by a more pronounced sensitivity to glycolysis inhibitors and elevated HIF1α expression. Silencing of HIF1α expression sensitized an intrinsically unresponsive MLL-rearranged leukemia cell to CCI-006, indicating that this pathway plays a role in determining sensitivity to the compound. In addition, unresponsive MLL-rearranged leukemia cells expressed increased levels of MEIS1, an important leukemogenic MLL target gene that plays a role in regulating metabolic phenotype through HIF1α. MEIS1 expression was also variable in a pediatric MLL-rearranged ALL patient dataset, highlighting the existence of a previously undescribed metabolic variability in MLL-rearranged leukemia that may contribute to the heterogeneity of the disease. This study thus identified a novel small molecule that rapidly kills MLL-rearranged leukemia cells by targeting a metabolic vulnerability in a subset of low HIF1α/low MEIS1-expressing MLL-rearranged leukemia cells.This research was supported by NHMRC, Leukemia Foundation, Anthony Rothe Memorial Trust, NSW Cancer Council, Cancer Institute NSW, Tenix Foundation, ISG Foundation and the Children’s Leukemia & Cancer Research Foundation, Perth

CCI-007, a novel small molecule with cytotoxic activity against infant leukemia with MLL rearrangements

There is an urgent need for the development of less toxic, more selective and targeted therapies for infants with leukemia characterized by translocation of the mixed lineage leukemia (MLL) gene. In this study, we performed a cell-based small molecule library screen on an infant MLL-rearranged (MLL-r) cell line, PER-485, in order to identify selective inhibitors for MLL-r leukemia. After screening initial hits for a cytotoxic effect against a panel of 30 cell lines including MLL-r and MLL wild-type (MLL-wt) leukemia, solid tumours and control cells, small molecule CCI- 007 was identified as a compound that selectively and significantly decreased the viability of a subset of MLL-r and related leukemia cell lines with CALM-AF10 and SET-NUP214 translocation. CCI-007 induced a rapid caspase-dependent apoptosis with mitochondrial depolarization within twenty-four hours of treatment. CCI-007 altered the characteristic MLL-r gene expression signature in sensitive cells with downregulation of the expression of HOXA9, MEIS1, CMYC and BCL2, important drivers in MLL-r leukemia, within a few hours of treatment. MLL-r leukemia cells that were resistant to the compound were characterised by significantly higher baseline gene expression levels of MEIS1 and BCL2 in comparison to CCI-007 sensitive MLL-r leukemia cells. In conclusion, we have identified CCI-007 as a novel small molecule that displays rapid toxicity towards a subset of MLL-r, CALM-AF10 and SET-NUP214 leukemia cell lines. Our findings suggest an important new avenue in the development of targeted therapies for these deadly diseases and indicate that different therapeutic strategies might be needed for different subtypes of MLL-r leukemia

Effective targeting of NAMPT in patient-derived xenograft models of high-risk pediatric acute lymphoblastic leukemia

The prognosis for children diagnosed with high-risk acute lymphoblastic leukemia (ALL) remains suboptimal, and more potent and less toxic treatments are urgently needed. We investigated the efficacy of a novel nicotinamide phosphoribosyltransferase inhibitor, OT-82, against a panel of patient-derived xenografts (PDXs) established from high-risk and poor outcome pediatric ALL cases. OT-82 was well-tolerated and demonstrated impressive single agent in vivo efficacy, achieving significant leukemia growth delay in 95% (20/21) and disease regression in 86% (18/21) of PDXs. In addition, OT-82 enhanced the efficacy of the established drugs cytarabine and dasatinib and, as a single agent, showed similar efficacy as an induction-type regimen combining three drugs used to treat pediatric ALL. OT-82 exerted its antileukemic action by depleting NAD+ and ATP, inhibiting the NAD+-requiring DNA damage repair enzyme PARP-1, increasing mitochondrial ROS levels and inducing DNA damage, culminating in apoptosis induction. OT-82 sensitivity was associated with the occurrence of mutations in major DNA damage response genes, while OT-82 resistance was characterized by high expression levels of CD38. In conclusion, our study provides evidence that OT-82, as a single agent, and in combination with established drugs, is a promising new therapeutic strategy for a broad spectrum of high-risk pediatric ALL for which improved therapies are urgently needed

BIODEGRADATION OF ACRYLIC PAINTS: PROCESS MODELLING OF BIOCIDE EFFECT ON BIOMASS GROWTH AT DIFFERENT TEMPERATURES

Abstract Acrylic paint, notwithstanding the attention paid during the production process, couldbe contaminated by bacteria. This is a consequence of microbiological residuals on the can, resulting in the alterationof paint characteristics. It is therefore necessary to provide an in-canpreservation of the paint by using a biocide.In this paper, the evolution of an in-can system, using a thermo-fluid dynamic model is presented; as a biocide, 2-methyl-4-isothiazolin-3-one, commercially known as MIT,was considered. The model was implemented on gPROMSsoftware and it was possible to determine the inhibitory concentration of the biocideinorder to guarantee both the protection of the can and the protection of thecover phase. To develop the model, kinetic parameters have been found by fitting available literature experimental data. As far as the thermodynamical parameters, theequilibrium between liquid and vapor phases was described bythe NRTLmodel (ASPEN Plus). The model has been validated through a comparison with experimental literature results using MIT alone and a mixture of biocides (MIT/BIT). The main results are that,at the maximum allowable concentration (100 ppm as imposed by law), the MIT biocide is able to protectthe paint for long periods, even when the temperature varies cyclically from 10 to 40°C