Genetic aspects and molecular testing in prostate cancer: a report from a Dutch multidisciplinary consensus meeting

Background: Germline and tumour genetic testing in prostate cancer (PCa) is becoming more broadly accepted, but testing indications and clinical consequences for carriers in each disease stage are not yet well defined.Objective: To determine the consensus of a Dutch multidisciplinary expert panel on the indication and application of germline and tumour genetic testing in PCa.Design, setting, and participants: The panel consisted of 39 specialists involved in PCa management. We used a modified Delphi method consisting of two voting rounds and a virtual consensus meeting.Outcome measurements and statistical analysis: Consensus was reached if >75% of the panellists chose the same option. Appropriateness was assessed by the RAND/UCLA appropriateness method.Results and limitations: Of the multiple-choice questions, 44% reached consensus. For men without PCa having a relevant family history (familial PCa/BRCA-related hered-itary cancer), follow-up by prostate-specific antigen was considered appropriate. For patients with low-risk localised PCa and a family history of PCa, active surveil-lance was considered appropriate, except in case of the patient being a BRCA2 germ -line pathogenic variant carrier. Germline and tumour genetic testing should not be done for nonmetastatic hormone-sensitive PCa in the absence of a relevant family history of cancer. Tumour genetic testing was deemed most appropriate for the identification of actionable variants, with uncertainty for germline testing. For tumour genetic testing in metastatic castration-resistant PCa, consensus was not reached for the timing and panel composition. The principal limitations are as fol-lows: (1) a number of topics discussed lack scientific evidence, and therefore the recommendations are partly opinion based, and (2) there was a small number of experts per discipline.Conclusions: The outcomes of this Dutch consensus meeting may provide further guidance on genetic counselling and molecular testing related to PCa.Patient summary: A group of Dutch specialists discussed the use of germline and tumour genetic testing in prostate cancer (PCa) patients, indication of these tests (which patients and when), and impact of these tests on the management and treatment of PCa.(c) 2022 The Author(s). Published by Elsevier B.V. on behalf of European Association of Urology. This is an open access article under the CC BY license (http://creativecommons. org/licenses/by/4.0/).Experimentele farmacotherapi

Reconstruction of Holocene monsoon history from the Pearl River Estuary, southern China, using diatoms and carbon isotope ratios

This study employs a multiproxy approach in the reconstruction of Holocene monsoon history from sedimentary sequences obtained from the Pearl River Estuary, southern China. A set of modern surface sediment samples were collected within and outside the estuary, and a sediment core was obtained from the mouth of the estuary. A range of modern environmental variables were recorded including water salinity (summer, winter and annual average) and water depth. The diatom results show a good relationship with water salinity, with marine diatoms dominating the more distal samples from outside the main estuary and freshwater diatoms dominating the proximal samples influenced by higher freshwater flux. This pattern is matched by the bulk organic carbon isotopes. The isotope values vary between −21.1±0.3‰ for samples from the fully marine environment, between −23.2±0.8‰ and −23.7±0.8‰ for samples from the mid to outer estuary brackish water environment and less than −24.7±1.3‰ for samples from the inner estuary close to the freshwater sources. Similarly, the C/N ratios vary from below 7±0.6 in the marine end-members to over 14.8±3.0 in the freshwater end-members. Both the diatom and carbon data from the sediment core reveal a significant increase in freshwater flux from 8500 cal. yr BP resulting from the enhanced summer monsoon regime in early Holocene. The strength of freshwater flux reached its highest between 7500 and 6000 cal. yr BP. In the last 6000 years, freshwater flux decreased towards present, reflecting a gradual weakening of the summer monsoon

Mid-Holocene variability of the East Asian monsoon based on bulk organic δ13C and C/N records from the Pearl River estuary, southern China

Understanding the mid-Holocene dynamics of the East Asian monsoon (EAM) is integral to improving models of the Holocene development of the global climate system. Here we reconstruct the mid-Holocene EAM history from the Pearl River estuary, southern China, using bulk organic carbon isotopes (δ13C), total carbon to total nitrogen (C/N) ratios and total organic carbon (TOC) concentration. Sedimentary δ13C, C/N and TOC are potentially good indicators of changes in monsoonal precipitation strength. Sediments buried during a period of high precipitation exhibit a high proportion of terrigenous material, and have low δ13C and high C/N, and vice versa during a period of low precipitation. Results suggest a general decreasing trend in monsoonal precipitation from 6650 to 2150 cal. yr BP because of the weakening Northern Hemisphere insolation most likely related to the current precession circle. Superimposed on this trend are apparent dry–wet oscillations at centennial to millennial timescales most likely in response to solar activity. Mismatches between our δ13C record and results from the Dongge Cave in southern China at millennial timescales may indicate that the δ13C from the Pearl River estuary reveals changes in precipitation over a broader area than the δ18O from Dongge Cave

Loss of CDC4/FBXW7 in gastric carinoma

Background: CDC4/FBXW7, encoding a ubiquitin ligase, maps to 4q32 and has been implicated as a tumor suppressor gene and therapeutic target in many tumor types. Mutations in colonic adenomas, and the frequent losses on 4q described in gastric cancer prompt speculation about the role of CDC4/FBXW7 in gastric carcinogenesis. Methods: We assessed the role of CDC4/FBXW7 in gastric cancer, through loss of heterozygosity (LOH) and multiplex ligation-dependent probe amplification (MLPA) on 47 flow-sorted gastric carcinomas including early-onset gastric cancers (EOGC) and xenografted conventional gastric carcinomas. Ploidy analysis was carried out on 39 EOGCs and immunohistochemistry of CDC4/FBXW7 and its substrates c-myc, c-jun, Notch and cyclin E was performed on 204 gastric carcinomas using tissue microarrays (TMAs). Sequence analysis of CDC4/FBXW7 was carried out on gastric carcinoma cell lines and xenografts. Results: Loss of heterozygosity of CDC4/FBXW7 occurred in 32% of EOGCs, and correlated with loss of expression in 26%. Loss of expression was frequent in both EOGC and conventional gastric cancers. No CDC4/FBXW7 mutations were found and loss of CDC4/FBXW7 did not correlate with ploidy status. There was a significant correlation between loss of CDC4/FBXW7 expression and upregulation of c-myc. Conclusion: Loss of CDC4/FBXW7 appears to play a role in both EOGC and conventional gastric carcinogenesis, and c-myc overexpression is likely to be an important oncogenic consequence of CDC4/FBXW7 loss.OV

Bulk organic δ13C and C/N as indicators for sediment sources in the Pearl River delta and estuary, southern China

Preservation of organic matter in estuarine and coastal areas is an important process in the global carbon cycle. This paper presents bulk d13C and C/N of organic matter from source to sink in the Pearl River catchment, delta and estuary, and discusses the applicability of d13C and C/N as indicators for sources of organic matter in deltaic and estuarine sediments. In addition to the 91 surface sediment samples, other materials collected in this study cover the main sources of organic material to estuarine sediment. These are: terrestrial organic matter (TOM), including plants and soil samples from the catchment; estuarine and marine suspended particulate organic carbon (POC) from both summer and winter. Results show that the average d13C of estuarine surface sediment increases from 25.0 1.3& in the freshwater environment to 21.0 0.2& in the marine environment, with C/N decreasing from 15.2 3.3 to 6.8 0.2. In the source areas, C3 plants have lower d13C than C4 plants (29.0 1.8& and 13.1 0.5& respectively). d13C increases from 28.3 0.8& in the forest soil to around 24.1& in both riverbank soil and mangrove soil due to increasing proportion of C4 grasses. The d13CPOC increases from 27.6 0.8& in the freshwater areas to 22.4 0.5& in the marine-brackish-water areas in winter, and ranges between 24.0& in freshwater areas and 25.4& in brackish-water areas in summer. Comparison of the d13C and C/N between the sources and sink indicates a weakening TOM and freshwater POC input in the surface sedimentary organic matter seawards, and a strengthening contribution from the marine organic matter. Thus we suggest that bulk organic d13C and C/N analysis can be used to indicate sources of sedimentary organic matter in estuarine environments. Organic carbon in surface sediments derived from anthropogenic sources such as human waste and organic pollutants from industrial and agricultural activities accounts for less than 10% of the total organic carbon (TOC). Although results also indicate elevated d13C of sedimentary organic matter due to some agricultural products such as sugarcane, C3 plants are still the dominant vegetation type in this area, and the bulk organic d13C and C/N is still an effective indicator for sources of organic matter in estuarine sediments

Loss of CDC4/FBXW7 in gastric carinoma

Background: CDC4/FBXW7, encoding a ubiquitin ligase, maps to 4q32 and has been implicated as a tumor suppressor gene and therapeutic target in many tumor types. Mutations in colonic adenomas, and the frequent losses on 4q described in gastric cancer prompt speculation about the role of CDC4/FBXW7 in gastric carcinogenesis. Methods: We assessed the role of CDC4/FBXW7 in gastric cancer, through loss of heterozygosity (LOH) and multiplex ligation-dependent probe amplification (MLPA) on 47 flow-sorted gastric carcinomas including early-onset gastric cancers (EOGC) and xenografted conventional gastric carcinomas. Ploidy analysis was carried out on 39 EOGCs and immunohistochemistry of CDC4/FBXW7 and its substrates c-myc, c-jun, Notch and cyclin E was performed on 204 gastric carcinomas using tissue microarrays (TMAs). Sequence analysis of CDC4/FBXW7 was carried out on gastric carcinoma cell lines and xenografts. Results: Loss of heterozygosity of CDC4/FBXW7 occurred in 32% of EOGCs, and correlated with loss of expression in 26%. Loss of expression was frequent in both EOGC and conventional gastric cancers. No CDC4/FBXW7 mutations were found and loss of CDC4/FBXW7 did not correlate with ploidy status. There was a significant correlation between loss of CDC4/FBXW7 expression and upregulation of c-myc. Conclusion: Loss of CDC4/FBXW7 appears to play a role in both EOGC and conventional gastric carcinogenesis, and c-myc overexpression is likely to be an important oncogenic consequence of CDC4/FBXW7 loss