Hereditary Prostate Cancer: Genes Related,Target Therapy and Prevention

Prostate cancer (PCa) is globally the second most diagnosed cancer type and the most common cause of cancer-related deaths in men. Family history of PCa, hereditary breast and ovarian cancer (HBOC) and Lynch syndromes (LS), are among the most important risk factors compared to age, race, ethnicity and environmental factors for PCa development. Hereditary prostate cancer (HPCa) has the highest heritability of any major cancer in men. The proportion of PCa attributable to hereditary factors has been estimated in the range of 5–15%. To date, the genes more consistently associated to HPCa susceptibility include mismatch repair (MMR) genes (MLH1, MSH2, MSH6, and PMS2) and homologous recombination genes (BRCA1/2, ATM, PALB2, CHEK2). Additional genes are also recommended to be integrated into specific research, including HOXB13, BRP1 and NSB1. Importantly, BRCA1/BRCA2 and ATM mutated patients potentially benefit from Poly (ADP-ribose) polymerase PARP inhibitors, through a mechanism of synthetic lethality, causing selective tumor cell cytotoxicity in cell lines. Moreover, the detection of germline alterations in MMR genes has therapeutic implications, as it may help to predict immunotherapy benefits. Here, we discuss the current knowledge of the genetic basis for inherited predisposition to PCa, the potential target therapy, and the role of active surveillance as a management strategy for patients with low-risk PCa. Finally, the current PCa guideline recommendations are reviewed.     

Hydrothermal Carbonization of Sewage Sludge: Analysis of Process Severity and Solid Content

Hydrothermal carbonization of sewage sludge was carried out with the aim to evaluate the influence of process severity and initial solid content. Response surface methodology was applied to model yield and C yield responses. Enhanced dewaterability performance was recorded under mild processing conditions. The treatment promoted concentration and immobilization of Pb, Cd, Ni, Zn, and Cu. Variation of the solid content showed a stronger influence than severity on average yield and C yield. Higher heating values (HHVs) and energy retention efficiencies (EREs) of hydrochars obtained at the lowest solid content displayed the lowest values. Hence, the energy requirements of a first dewatering step should be compared with the related improvement in terms of HHV and ERE when sludge is used as feedstock.     

Hydromorphological,hydraulic and ecological effects of restored wood: findings and reflections from an academic partnership approach

Large wood (re)introduction can deliver multiple benefits in river restoration, but there is a dearth of the detailed and longer‐term post‐project monitoring and evaluation required for improving best practice. We present findings from an academic partnership approach to post‐project evaluation, based on successive MSc research projects on restored large wood in the Loddon catchment, UK. Field and modelling data reveal: (i) key differences in large wood features between restored and natural reaches; (ii) increased hydraulic retention and changes to mesohabitats associated with large wood; (iii) differences in macroinvertebrate community composition around large wood but a lack of site‐level effects; (iv) interactions between macrophytes and large wood that may be specific to restored reaches; (v) a need for further field and modelling studies to inform the accurate representation of large wood in hydraulic models. Some key challenges in partnership working are identified to aid planning and effectiveness of future collaborations.     

Altered Fatty Acid Metabolism-Related Gene Expression in Liver from Morbidly Obese Women with Non-Alcoholic Fatty Liver Disease

Lipid accumulation in the human liver seems to be a crucial mechanism in the pathogenesis and the progression of non-alcoholic fatty liver disease (NAFLD). We aimed to evaluate gene expression of different fatty acid (FA) metabolism-related genes in morbidly obese (MO) women with NAFLD. Liver expression of key genes related to de novo FA synthesis (LXRα, SREBP1c, ACC1, FAS), FA uptake and transport (PPARγ, CD36, FABP4), FA oxidation (PPARα), and inflammation (IL6, TNFα, CRP, PPARδ) were assessed by RT-qPCR in 127 MO women with normal liver histology (NL, n = 13), simple steatosis (SS, n = 47) and non-alcoholic steatohepatitis (NASH, n = 67). Liver FAS mRNA expression was significantly higher in MO NAFLD women with both SS and NASH compared to those with NL (p = 0.003, p = 0.010, respectively). Hepatic IL6 and TNFα mRNA expression was higher in NASH than in SS subjects (p = 0.033, p = 0.050, respectively). Interestingly, LXRα, ACC1 and FAS expression had an inverse relation with the grade of steatosis. These results were confirmed by western blot analysis. In conclusion, our results indicate that lipogenesis seems to be downregulated in advanced stages of SS, suggesting that, in this type of extreme obesity, the deregulation of the lipogenic pathway might be associated with the severity of steatosis.     

The Tumor Microenvironment in Liver Metastases from Colorectal Carcinoma in the Context of the Histologic Growth Patterns

Colorectal carcinoma (CRC) is the third most common cancer. Likewise, it is a disease that has a long survival if it is prematurely detected. However, more than 50% of patients will develop metastases, mainly in the liver (LM-CRC), throughout the evolution of their disease, which accounts for most CRC-related deaths. Treatment it is certainly a controversial issue, since it has not been shown to increase overall survival in the adjuvant setting, although it does improve disease free survival (DFS). Moreover, current chemotherapy combinations are administered based on data extrapolated from primary tumors (PT), not considering that LM-CRC present a very particular tumor microenvironment that can radically condition the effectiveness of treatments designed for a PT. The liver has a particular histology and microenvironment that can determine tumor growth and response to treatments: double blood supply, vascularization through fenestrated sinusoids and the presence of different mesenchymal cell types, among other particularities. Likewise, the liver presents a peculiar immune response against tumor cells, a fact that correlates with the poor response to immunotherapy. All these aspects will be addressed in this review, putting them in the context of the histological growth patterns of LM-CRC, a particular pathologic feature with both prognostic and predictive repercussions.     

Specificity of Lipoprotein Chaperones for the Characteristic Lipidated Structural Motifs of their Cognate Lipoproteins

Lipoprotein‐binding chaperones mediate intracellular transport of lipidated proteins and determine their proper localisation and functioning. Understanding of the exact structural parameters that determine recognition and transport by different chaperones is of major interest. We have synthesised several lipid‐modified peptides, representative of different lipoprotein classes, and have investigated their binding to the relevant chaperones PDEδ, UNC119a, UNC119b, and galectins‐1 and ‐3. Our results demonstrate that PDEδ recognises S‐isoprenylated C‐terminal peptidic structures but not N‐myristoylated peptides. In contrast, UNC119 proteins bind only mono‐N‐myristoylated, but do not recognise doubly lipidated and S‐isoprenylated peptides at the C terminus. For galectins‐1 and ‐3, neither binding to N‐acylated, nor to C‐terminally prenylated peptides could be determined. These results shed light on the specificity of the chaperone‐mediated cellular lipoprotein transport systems.     

A test house study of pesticides and pesticide degradation products following an indoor application

Preexisting pesticide degradates are a concern for pesticide biomonitoring studies as exposure to them may result in overestimation of pesticide exposure. The purpose of this research was to determine whether there was significant formation and movement, of pesticide degradates over a 5‐week period in a controlled indoor setting after insecticide application. Movement of the pesticides during the study was also evaluated. In a simulated crack and crevice application, commercially available formulations of fipronil, propoxur, cis/trans‐permethrin, and cypermethrin were applied to a series of wooden slats affixed to the wall in one room of an unoccupied test house. Floor surface samples were collected through 35 days post‐application. Concentrations of the pesticides and the following degradates were determined: 2‐iso‐propoxyphenol, cis/trans 3‐(2,2‐dichlorovinyl)‐3‐3‐dimethyl‐(1‐cyclopropane) carboxylic acid, 3‐phenoxybenzoic acid, fipronil sulfone, fipronil sulfide, and fipronil desulfinyl. Deltamethrin, which had never been applied, and chlorpyrifos, which had been applied several years earlier, and their degradation products, cis‐3‐(2,2‐dibromovinyl)‐2,2‐dimethylcyclopropane‐1‐carboxylic acid, and, 3,5,6‐trichloro‐2‐pyridinol, respectively, were also measured. Propoxur was the only insecticide with mass movement away from the application site. There was no measurable formation or movement of the degradates. However, all degradates were present at low levels in the formulated product. These results indicate longitudinal repetitive sampling of indoor degradate levels during short‐term studies, is unnecessary.     

Rate-Controlling Mechanisms in the Photo-degradation of 5-Hydroxymethylfurfural

Rate-controlling mechanisms in the photo-degradation of 5-hydroxymethylfurfural (HMF) were studied applying kinetic and thermodynamic compensations. Aqueous solutions of HMF were prepared at a concentration of 100 mg L^?1 and at pH values of 3, 3.4, 4, and 5. The UV irradiation of samples was performed in an installation consisting of a black chamber containing the reactor and a mid-pressure mercury lamp with emission wavelengths between 250 and 740 nm. Every sample was irradiated at 12, 25, 35, and 45 °C for 120 min, analyzing their HMF content each 10 min. The photo-degradation data fitted well to zero-order kinetic model, and the constant values were used to study whether the kinetic and thermodynamic compensation could be applied. The isokinetic temperature was very similar for kinetic compensation (T_B?=?278.0 K) and thermodynamic compensation (T_B?=?277.8 K). Applying the Leffler’s criterion, the HMF photo-degradation was entropically controlled, probably as a consequence of hydrophobic interactions. In order to check the entropical control, two experiments were repeated at pH 3 but avoiding agitation. As the new obtained kinetic constants were highly different from the values previously obtained using agitation, it can be concluded that the HMF photo-degradation is an entropy-controlled process and can be speeded up by changing non-thermal parameters, like agitation.