Great Britain Research Articles

Imaging timing after surgery for glioblastoma: an evaluation of practice in Great Britain and Ireland (INTERVAL-GB)- a multi-centre, cohort study

PurposePost-operative MRI is used to assess extent of resection, monitor treatment response and detect progression in high-grade glioma. However, compliance with accepted guidelines for follow-up MRI, and impact on management/outcomes is unclear.MethodsMulti-center, retrospective observational cohort study of patients with confirmed WHO grade 4 glioma (August 2018-February 2019) receiving oncological treatment. Primary objective: investigate follow-up MRI surveillance practice and compliance with recommendations from NICE (Post-operative scan < 72h, MRI every 3–6 months) and EANO (Post-operative scan < 48h, MRI every 3 months).ResultsThere were 754 patients from 26 neuro-oncology centers with a median age of 63 years (IQR 54–70), yielding 10,100 (median, 12.5/person, IQR 5.2–19.4) person-months of follow-up. Of patients receiving debulking surgery, most patients had post-operative MRI within 72 h of surgery (78.0%, N = 407/522), and within 48 h of surgery (64.2%, N = 335/522). The median number of subsequent follow-up MRI scans was 1 (IQR 0–4). Compliance with NICE and EANO recommendations for follow-up MRI was 52.8% (N = 398/754) and 24.9% (N = 188/754), respectively. On multivariable Cox regression analysis, increased time spent in recommended follow-up according to NICE guidelines was associated with longer OS (HR 0.56, 95% CI 0.46–0.66, P < 0.001), but not PFS (HR 0.93, 95% CI 0.79–1.10, P = 0.349). Increased time spent in recommended follow-up according to EANO guidelines was associated with longer OS (HR 0.54, 95% CI 0.45–0.63, P < 0.001) but not PFS (HR 0.99, 95% CI 0.84–1.16, P = 0.874).ConclusionRegular surveillance follow-up for glioblastoma is associated with longer OS. Prospective trials are needed to determine whether regular or symptom-directed MRI influences outcomes.Graphical

German-Speaking Émigré Economists in Great Britain and the Analysis of the German War Economy

Abstract The need for analysis of the German war economy became urgent after the defeat of France and the threat of an invasion of Britain by Nazi Germany after the battle of Dunkirk in the summer of 1940. The expertise of émigré scholars now was in strong demand. First, this essay discusses the series of twelve articles that Hans Singer contributed at the request of Keynes to the Economic Journal from 1940 to 1944. An important characteristic of war economies is a shortage of consumer goods, which raises the question of the appropriate rationing scheme. Therefore, the notion of a virtual price system, introduced by Erwin Rothbarth, which takes note of the welfare consequences of interventions into the free choices of consumers, is the focus of the next section. Hal C. Hillmann was a leading analyst of the German war economy, the comparative strength of the great powers, and postwar reconstruction. Finally, the article discusses the role of Nicholas Kaldor, who had firsthand knowledge as a key member of the research team of highbrow economists chaired by John Kenneth Galbraith that at the end of the war studied the effects of Allied bombing on the German war economy. Kaldor's experience, also as the director of the Research and Planning Division of the UN Economic Commission for Europe from 1947 to 1949, significantly influenced his pioneering contributions to growth theory.

Combining global precipitation data and machine learning to predict flood peaks in ungauged areas with similar climate

Increasing flood risk due to urbanization and climate change poses a significant challenge to societies at global scale. Hydrologic information that is required for understanding flood processes and for developing effective warning procedures is currently lacking in most parts of the world. Procedures that can combine global climate dataset from satellite and reanalysis with fast and low computational cost prediction systems, are attractive solutions for addressing flood predictions in ungauged areas. This work develops and tests a prediction framework that relies on two fundamental components. First, meteorological data from global datasets (IMERG and ERA5-Land) provide key input variables and second, ML models trained in the data-rich contiguous US, are applied in climatically similar regions in other parts of the world. Catchments in Australia, Brazil, Chile, Switzerland, and Great Britain were used as pseudo-ungauged regions for testing. Results indicate acceptable performance for both IMERG and ERA5-Land forced models with relative difference in flood peak prediction within 30 % and similar overall performance to locally trained ML models. Specific climate regions for which ML models have revealed good performance include Mediterranean climates like the US West Coast, subtropical areas like the Southern Atlantic Gulf, and mild temperate regions like the Mid-Atlantic Basin. This work highlights the potential of combining global precipitation dataset with pre-trained ML models in data-rich areas, for flood prediction in ungauged areas with similar climate.

The unique metabolome of clear cell ovarian carcinoma.

Clear cell ovarian carcinoma (CCOC) is an aggressive malignancy affecting younger women. Despite ovarian cancer subtypes having diverse molecular and clinical characteristics, the mainstay of treatment for advanced stage disease remains cytotoxic chemotherapy. Late stage CCOC is resistant to conventional chemotherapy, which means a suboptimal outcome for patients affected. Despite detailed genomic, epigenomic, transcriptomic, and proteomic characterisation, subtype-specific treatment for CCOC has shown little progress. The unique glycogen accumulation defining CCOC suggests altered metabolic pathway activity and dependency. This study presents the first metabolomic landscape of ovarian cancer subtypes, including 42 CCOC, 20 high-grade serous and 21 endometrioid ovarian carcinomas, together comprising the three most common ovarian carcinoma subtypes. We describe a distinct metabolomic landscape of CCOC compared with other ovarian cancer subtypes, including alterations in energy utilisation and cysteine metabolism. In addition, we identify CCOC-specific alterations in metabolic pathways including serine biosynthesis and ROS-associated pathways that could serve as potential therapeutic targets. Our study provides the first in-depth study into the metabolome of ovarian cancers and a rich resource to support ongoing research efforts to identify subtype-specific therapeutic targets that could improve the dismal outcome for patients with this devastating malignancy. © 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Spatial effects of infiltrating T cells on neighbouring cancer cells and prognosis in stage III CRC patients.

Colorectal cancer (CRC) is one of the most frequently occurring cancers, but prognostic biomarkers identifying patients at risk of recurrence are still lacking. In this study, we aimed to investigate in more detail the spatial relationship between intratumoural T cells, cancer cells, and cancer cell hallmarks as prognostic biomarkers in stage III colorectal cancer patients. We conducted multiplexed imaging of 56 protein markers at single-cell resolution on resected fixed tissue from stage III CRC patients who received adjuvant 5-fluorouracil (5FU)-based chemotherapy. Images underwent segmentation for tumour, stroma, and immune cells, and cancer cell 'state' protein marker expression was quantified at a cellular level. We developed a Python package for estimation of spatial proximity, nearest neighbour analysis focusing on cancer cell-T-cell interactions at single-cell level. In our discovery cohort (Memorial Sloan Kettering samples), we processed 462 core samples (total number of cells: 1,669,228) from 221 adjuvant 5FU-treated stage III patients. The validation cohort (Huntsville Clearview Cancer Center samples) consisted of 272 samples (total number of cells: 853,398) from 98 stage III CRC patients. While there were trends for an association between the percentage of cytotoxic T cells (across the whole cancer core), it did not reach significance (discovery cohort: p = 0.07; validation cohort: p = 0.19). We next utilised our region-based nearest neighbour approach to determine the spatial relationships between cytotoxic T cells, helper T cells, and cancer cell clusters. In both cohorts, we found that shorter distance between cytotoxic T cells, T helper cells, and cancer cells was significantly associated with increased disease-free survival. An unsupervised trained model that clustered patients based on the median distance between immune cells and cancer cells, as well as protein expression profiles, successfully classified patients into low-risk and high-risk groups (discovery cohort: p = 0.01; validation cohort: p = 0.003). © 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Learning from a Pattern in Black Baptist Women’s Formation for Ordained Ministry at English Baptist Colleges

ABSTRACT This article firstly identifies an early pattern of Black Baptist women predominantly choosing to undertake formation for ministry at one of the Baptist Union of Great Britain’s (Baptist Union’s) colleges, namely, Spurgeon’s, over and above Bristol, Northern, and Regent’s Park. Secondly, it highlights the contextual particularities of each of these four Baptist colleges – from the 1980s onwards – with reference to women’s and Black people’s engagement, and the potential for all of the colleges to better document and share their history with reference to women and Black people’s engagement in order to cultivate a sense of welcome and belonging for all.

NMRK2 is an efficient diagnostic indicator for Xp11.2 translocation renal cell carcinoma.

Xp11.2 translocation renal cell carcinomas (tRCC) are a rare and highly malignant type of renal cancer, lacking efficient diagnostic indicators and therapeutic targets. Through the analysis of public databases and our cohort, we identified NMRK2 as a potential diagnostic marker for distinguishing Xp11.2 tRCC from kidney renal clear cell carcinoma (KIRC) and kidney renal papillary cell carcinoma (KIRP) due to its specific upregulation in Xp11.2 tRCC tissues. Mechanistically, we discovered that TFE3 fusion protein binds to the promoter of the NMRK2 gene, leading to its upregulation. Importantly, we established RNA- and protein-based diagnostic methods for identifying Xp11.2 tRCC based on NMRK2 expression levels, and the diagnostic performance of our methods was comparable to a dual-color break-apart fluorescence in situ hybridization assay. Moreover, we successfully identified fresh Xp11.2 tRCC tissues after surgical excision using our diagnostic methods and established an immortalized Xp11.2 tRCC cell line for further research purposes. Functional studies revealed that NMRK2 promotes the progression of Xp11.2 tRCC by upregulating the NAD+/NADH ratio, and supplementation with β-nicotinamide mononucleotide (NMN) or nicotinamide riboside chloride (NR), effectively rescued the phenotypes induced by the knockdown of NMRK2 in Xp11.2 tRCC. Taken together, these data introduce a new diagnostic indicator capable of accurately distinguishing Xp11.2 tRCC and highlight the possibility of developing novel targeted therapeutics. © 2024 The Pathological Society of Great Britain and Ireland.

Enemy Aliens: internment and deportation policy in Great Britain, September 1939–June 1940

AbstractDuring the Second World War, Germans, Austrians and Italians living in Great Britain were designated as ‘enemy aliens’ and consequently interned. The worsening situation on the continent in May and June 1940 stirred up hysteria that spies and saboteurs could be amongst the Germans and Austrians. Mass arrests started in May 1940, and Italians were soon caught up in the detentions when Mussolini declared war on 10 June, thus filling internment camps to capacity. Canada and Australia agreed to take some of the ‘most dangerous characters’, facilitating the most controversial aspect of internment – deportation – which led to the ultimate tragedy when the SS Arandora Star was torpedoed and sunk on 2 July 1940. Building on previous scholarship that focuses on either German or Italian internment, this article examines both government policy towards and the internee experience of these two groups on an equal footing, thus furthering integration of the Italian narrative within internment historiography.

Everyday Life in Great Britain and Poland During the Covid-19 Pandemic and Brexit

In recent years, everyday life and interpersonal relationships in a broad sense have been shaped by the SarsCov-2 pandemic and its extensive consequences – both on a local and on a global level. Other phenomena have made their presence felt at a local and global level too – Brexit, for example. In this article, based on research carried out in Poland, England and Northern Ireland in August and September 2021, we present various dimensions of everyday life and the relationships of migrants with people who are important to them in Poland – in the context of these two main processes. The results of our research indicate that the new circumstances affect the everyday lives of migrants and their relatives in Poland on various levels, such as routine activities, work, interpersonal relations, and transnational contacts. We have also identified the stages of these processes and the accompanying emotions, and the pandemic emerged as the leading theme, overshadowing Brexit.

Ventilation and Public Health: A Fraught History.

Since the beginning of the COVID-19 pandemic, a vigorous public health discussion has arisen over indoor air quality and ventilation. In popular press articles, bestselling books, and the US Environmental Protection Agency's recently announced Clean Air in Buildings Challenge, scholars and policy experts have claimed that improved ventilation systems can lead to better productivity and performance. By reevaluating those claims in light of the history of public health in Great Britain and the United States, we found that better ventilation has frequently been proposed as a cost-effective and nonintrusive means of improving health in institutions experiencing structural and environmental public health problems. Furthermore, our examination of efforts to provide ventilation for enslaved people, incarcerated people, and the urban poor revealed a consistent lack of government regulation and a disassociation of air quality concerns from broader environmental, social, and economic realities. By continuing to ignore these broader contexts, current ventilation efforts risk repeating this pattern. (Am J Public Health. 2024;114(8):798-804. https://doi.org/10.2105/AJPH.2024.307670).

WINTER MEETING, 6th Joint Meeting with the Royal Society of Medicine, 215th Scientific Meeting of the Pathological Society of Great Britain & Ireland, 30-31 January 2024.

WINTER MEETING, 6th Joint Meeting with the Royal Society of Medicine, 215th Scientific Meeting of the Pathological Society of Great Britain & Ireland, 30-31 January 2024.

National health examination surveys; a source of critical data.

The aim of this paper is to contribute technical arguments to the debate about the importance of health examination surveys and their continued use during the post-pandemic health financing crisis, and in the context of a technological innovation boom that offers new ways of collecting and analysing individual health data (e.g. artificial intelligence). Technical considerations demonstrate that health examination surveys make an irreplaceable contribution to the local availability of primary health data that can be used in a range of further studies (e.g. normative, burden-of-disease, care cascade, cost and policy impact studies) essential for informing several phases of the health planning cycle (e.g. surveillance, prioritization, resource mobilization and policy development). Examples of the use of health examination survey data in the World Health Organization (WHO) European Region (i.e. Finland, Italy, Malta and the United Kingdom of Great Britain and Northern Ireland) and the WHO Region of the Americas (i.e. Chile, Mexico, Peru and the United States of America) are presented, and reasons why health provider-led data cannot replace health examination survey data are discussed (e.g. underestimation of morbidity and susceptibility to bias). In addition, the importance of having nationally representative random samples of the general population is highlighted and we argue that health examination surveys make a critical contribution to external quality control for a country's health system by increasing the transparency and accountability of health spending. Finally, we consider future technological advances that can improve survey fieldwork and suggest ways of ensuring health examination surveys are sustainable in low-resource settings.

Future impacts of river flow on hydropower generation in Great Britain

ABSTRACT Climate change is likely to alter Great Britain's water resource availability for hydropower generation. This affects hydropower production due to uncertainty around the timing and magnitude of water availability, particularly run of river (RoR) schemes that lack the storage capacity to buffer seasonal flow variability. This study examines the likely future changes on RoR potential at locations across GB using the enhanced future flows (eFLaG) dataset. Results show that annual river flows are projected to increase in winter and spring but reduce in summer and autumn. This has an impact on RoR potential with a projected decrease in the near (2030–2059) and far future (2050–2079) for both summer (−19%, −32%) and autumn (−11%, −19%) throughout GB. Therefore, results indicate a decrease in the annual RoR potential in GB. This study underscores the importance of incorporating climate change considerations in the planning and operation of RoR schemes to ensure sustainable energy generation. This could be achieved by upgrading existing turbines to handle higher flows or designing new turbines capable of accommodating larger discharges to fully utilise the increased flows during winter. However, this should be done with consideration of the technical limitations and the opportunities for optimisations for system generation.

Riverine concentrations and export of dissolved silicon, and potential controls on nutrient stoichiometry, across the land–ocean continuum in Great Britain

Silicon (Si) is an essential nutrient element in freshwater and marine ecosystems, and its abundance relative to macro-nutrients (N, P) can impact phytoplankton communities in eutrophic rivers and estuaries. This study is the first national assessment examining (i) the primary sources (geological, biological, landcover) and controls (geomorphological, precipitation) on the transport of terrestrial dissolved silicon across Great Britain to the ocean, and (ii) the current extent and nature of its interactions with macro-nutrients in these catchments in relation to its potential impacts on phytoplankton community structure. It uses results from a year-long survey of 41 rivers along with historical data. Highest concentrations of dissolved Si (4–5.5 mg L-1) were found in rivers of the chalk- and sedimentary sandstone-based catchments of southern Great Britain and the hard sandstone catchments of Scotland. Catchment yield rates for dissolved Si varied between 0.2 and 2.6 t km−2 yr−1, with highest yields found in catchments with higher precipitation and runoff. Analysis of river N:P and dissolved Si:N ratios suggested that the sampled rivers were typically N enriched, and P limited with respect to dissolved Si. Molar dissolved Si:N ratios < 1, an indicator of river eutrophication, were associated with total nitrogen concentrations exceeding 1.8 mg L-1 or greater. The Indicator of Coastal Eutrophication index was used to assess the potential role of dissolved Si in the eutrophication of coastal waters. Negative values indicating limited eutrophication potential to non-siliceous algae were generally found, although some rivers had annual Indicator of Coastal Eutrophication index values exceeding 0, with values as high as 35 kg C km−2 day−1. In many eutrophic rivers, high dissolved Si concentrations derived from catchment lithology, kept the Indicator of Coastal Eutrophication index values below zero. Results have demonstrated that high N and P export have likely shifted most Great Britain rivers and coastal waters beyond the stoichiometric range where diatoms dominate production and into one where non-siliceous algae maybe increasingly present. Thus, future assessments of macro-nutrient management schemes, such as those involving wetlands should include dissolved Si routinely due to its stoichiometric importance.

High fibrinogen content in pregnant women – pathology or overdiagnosis?

An increased fibrinogen (FG) concentration during pregnancy is considered a protective mechanism against bleeding during childbirth. An enlarged amount of FG increases the aggregation of erythrocytes, blood plasma viscosity, microvascular resistance – permanent elements of the pathogenesis of arterial hypertension, stroke, coronary heart disease. It is also associated with an increased likelihood of development of preeclampsia and stroke with subsequent neurological disorders.In addition to its undeniable importance for hemostasis, FG is directly related to several physiological and pathophysiological conditions, such as infection, wound healing, tumorigenesis, and the severity of atherosclerosis. It also has a decisive role in the development of pregnancy. Maternal FG is necessary for the progress of pregnancy, as it stabilizes the utero-placental connection at the fibrinoid layer of the fetal-maternal junction. No reports on the study of pathological forms of FG in Ukraine were found.The objective: to compare the indicators of FG concentration and related elements of the blood coagulation system of pregnant and parturient women in different gestational periods and after childbirth.Materials and methods. Blood components from the ulnar vein of 30 women in labor at a gestation period of 22–27 weeks (extremely preterm birth (EPB) – I group), 37 women in labor at a term of 28–34 weeks (early preterm birth (PB) – II group) and 40 women with gestational period 37–41 weeks (control group (CG) – III group) was studied. In the collected samples the content of FG, D-dimer (Dd), prothrombin index (PI), activated partial thromboplastin time (APTT), as well as the levels of hemoglobin (Hb), hematocrit (Ht) and total protein (TP) of the blood plasma were determined.All women in labor were hospitalized in the active phase of the I labor period and did not receive infusion therapy. In terms of gestation, corresponding to EPB, early PB and CG, 10 pregnant women who were on outpatient registration at the Perinatal Center were examined for comparison of the studied indicators outside of labor.Indicators of the biochemical coagulogram were studied on a Helena C-2 semi-automatic coagulometer (Helena Biosciences, Great Britain).Results. The FG concentration increased from 4.2±0.56 g/l in the term 22–27 weeks to 4.4±0.57 g/l before delivery with a diapason of 3.5 to 5.0 g/l. In all parturients, the FG concentration was lower than 4.5 g/l, respectively by group: 4.5±0.81; 4.1±0.74 and 4.1±0.65 g/l (р&lt;0.05). In 24 hours after delivery the FG concentration increased in CG to 5.0±0.82 g/l, and after 48 hours – to 5.3±1.19 g/l, which exceeded the indicators of parturients of the EPB and early PB groups and pregnant women of these same terms, in which the highest indicator was 4.5±0.81 g/l in the EPB group (p&lt;0.05).An increase in the Dd index with growing gestational age was observed in all pregnant women (from 274±133.3 to 501±174.7 μg/l). It continued during the first postpartum day – up to 685±157.5 μg/l, decreased on the second day – 429±198.9 μg/l (p&lt;0.05), approaching the indicators of the EPB and early PB groups (487±267.0 and 397±202.3 μg/l; p&gt;0.05) and pregnant women of the same term.Hb decreased to 106±8.9 g/l, and Ht – to 35±6.1% with the progression of pregnancy. In parturients of the PB group, they were probably higher than the indicators of pregnant women of the corresponding terms, increasing on the second day after delivery – 110±6.7 g/l and 41±3.1%.There was no significant blood loss in the clinical groups. In all pregnant and parturient women the APTT and PI indicators varied from 27.0±3.51 s to 35.4±3.43 s and from 88±4.8% to 101±5.2%, respectively.Conclusions. 1. A gradual increase in the fibrinogen (FG) concentration with increasing gestational age from 4.2±0.56 g/l in 22–27 weeks to 4.4±0.57 g/l by the time of delivery indicates an increase in the level of FG in healthy pregnant women as an adaptive response of the body to the formation of an additional vascular system.2. An excessive FG increase is a consequence of hemoconcentration, not absolute hyperfibrinogenemia, and may be a sign of pathological processes underlying hypovolemia. In case of extremely preterm birth (EPB), the concentration of FG in the parturient was 4.5±0.81 g/l. Higher values of FG, hemoglobin, and hematocrit in parturients with EPB than in pregnant women at the same term are evidence of insufficient hemodilution, which can be considered as one of the pathogenetic mechanisms of premature labor.3. Laboratory indicators of the blood coagulation system – APTT, PI – in the absence of bleeding have no diagnostic value.

Changes in the tumour microenvironment mark the transition from serous borderline tumour to low-grade serous carcinoma.

Low-grade serous ovarian carcinoma (LGSC) is a rare and lethal subtype of ovarian cancer. LGSC is pathologically, biologically, and clinically distinct from the more common high-grade serous ovarian carcinoma (HGSC). LGSC arises from serous borderline ovarian tumours (SBTs). The mechanism of transformation for SBTs to LGSC remains poorly understood. To better understand the biology of LGSC, we performed whole proteome profiling of formalin-fixed, paraffin-embedded tissue blocks of LGSC (n = 11), HGSC (n = 19), and SBTs (n = 26). We identified that the whole proteome is able to distinguish between histotypes of the ovarian epithelial tumours. Proteins associated with the tumour microenvironment were differentially expressed between LGSC and SBTs. Fibroblast activation protein (FAP), a protein expressed in cancer-associated fibroblasts, is the most differentially abundant protein in LGSC compared with SBT. Multiplex immunohistochemistry (IHC) for immune markers (CD20, CD79a, CD3, CD8, and CD68) was performed to determine the presence of B cells, T cells, and macrophages. The LGSC FAP+ stroma was associated with greater abundance of Tregs and M2 macrophages, features not present in SBTs. Our proteomics cohort reveals that there are changes in the tumour microenvironment in LGSC compared with its putative precursor lesion, SBT. These changes suggest that the tumour microenvironment provides a supportive environment for LGSC tumourigenesis and progression. Thus, targeting the tumour microenvironment of LGSC may be a viable therapeutic strategy. © 2024 The Pathological Society of Great Britain and Ireland.

How, when and who should ask about pregnancy intentions in primary care? A qualitative study of primary health care professionals' preferences.

Knowing people's pregnancy intentions would help health care professionals (HCPs) to take a holistic approach to reproductive health, and particularly to providing preconception care. To assess the feasibility of implementation of questions about pregnancy preferences in a range of primary care settings in Great Britain, including digital implementation. Qualitative study using online semi-structured interviews with primary care professionals across Great Britain in 2022. Twelve online interviews were conducted with GPs (n=3), practice nurses (n=3), sexual and reproductive health professionals (n=4) and health visitors (n=2). Framework analysis was conducted in Nvivo, adapting a coding frame from complementary interviews with women. HCPs perceived asking about pregnancy preferences as valuable in meeting patients' reproductive health needs and most suited to women's health consultations, medication and disease reviews, baby checks, or as an addition to lifestyle questions leading to health promotion advice. An introductory, non-discriminatory signposting sentence was well-liked, and the preferred question in a face-to-face clinical encounter was asking how the person would feel about a pregnancy in the next year, in line with women's preference. Guidance and training would give clinicians confidence in knowing how to ask about pregnancy preferences and advise their patients accordingly. Asking about pregnancy intentions is acceptable to women and HCPs and feasible in primary care, but implementation needs to be adapted to the patient and context. Digital options that enable patients to self-manage can reduce the need for HCP input and avoid medicalising a normal process.

INTERNATIONAL EXPERIENCE IN USING INNOVATIVE TOOLS OF STATE FINANCIAL CONTROL OVER ILLEGAL FINANCIAL FLOWS

Effective financial control often requires cooperation between countries and international organizations. The study of international experience contributes to the development of mechanisms of international cooperation and information exchange to combat illegal financial flows. The article examines the international experience of using innovative tools of state financial control to combat illegal financial flows. Emphasis is placed on the analysis of modern practices in countries with developed systems of financial control, such as the USA, Great Britain, Germany, France, and Japan. The main tools used to detect and prevent illegal financial flows are described, including automated transaction monitoring systems, analytical platforms based on artificial intelligence, as well as methods of a risk-based approach to auditing. Special attention is paid to the role of international cooperation and information exchange between financial institutions of different countries, which allows more effective detection and termination of activities related to money laundering and terrorist financing. The article also analyzes the legal acts that regulate the use of innovative financial control tools in different countries and their compliance with international standards, such as FATF recommendations. The challenges and risks associated with the introduction of the latest technologies into the financial control system, including issues of data confidentiality and protection of human rights, were studied. The analysis of indicators and methods of assessment of illegal financial flows was carried out, the formation of illegal financial flows in modern globalized conditions was analyzed, the experience of other countries with regard to state financial control and its effectiveness was studied, innovative approaches and technologies that could be used to improve the financial control system and the possibility of their implementation of financial control in Ukraine. In addition, the evaluation of the effectiveness of the proposed innovative tools in the fight against illegal financial flows was carried out and the need for the development of such an assessment methodology, which would allow measuring the real impact of new technologies on reducing the volume of illegal financial flows, was substantiated.

TRKing down drug resistance in NTRK fusion-positive cancers†.

In a recent issue of The Journal of Pathology, Chen and colleagues established novel patient-derived ex vivo models of NTRK fusion-positive soft tissue sarcoma to characterize resistance mechanisms against targeted therapy with tyrosine kinase inhibitors. Prolonged exposure to escalating concentrations of the tyrosine kinase inhibitor, entrectinib, ultimately led to the occurrence of resistant clones that harbored an inactivating mutation in the NF2 gene, not previously described in this context, accompanied by increased PI3K/AKT/mTOR and Ras/Raf/MEK/ERK signaling. Finally, an inhibitor screen identified, among others, MEK and mTOR inhibitors as potential combination agents. © 2024 The Pathological Society of Great Britain and Ireland.

Nerve growth factor inducible (VGF) is a secreted mediator for metastatic breast cancer tropism to the brain.

Brain metastases are one of the most serious clinical problems in breast cancer (BC) progression, associated with lower survival rates and a lack of effective therapies. Thus, to dissect the early stages of the brain metastatic process, we studied the impact of brain organotropic BC cells' secretomes on the establishment of the brain pre-metastatic niche (PMN). We found that BC cells with specific tropism to the brain caused significant blood-brain barrier (BBB) disruption, as well as microglial activation, in both in vitro and in vivo models. Further, we searched for a brain-organotropic metastatic signature, as a promising source for the discovery of new biomarkers involved in brain metastatic progression. Of relevance, we identified VGF (nerve growth factor inducible) as a key mediator in this process, also impacting the BBB and microglial functions both in vitro and in vivo. In a series of human breast tumors, VGF was found to be expressed in both cancer cells and the adjacent stroma. Importantly, VGF-positive tumors showed a significantly worse prognosis and were associated with HER2 (human epidermal growth factor receptor 2) overexpression and triple-negative molecular signatures. Further clinical validation in primary tumors from metastatic BC cases showed a significant association between VGF and the brain metastatic location, clearly and significantly impacting on the prognosis of BC patients with brain metastasis. In conclusion, our study reveals a unique secretome signature for BC with a tropism for the brain, highlighting VGF as a crucial mediator in this process. Furthermore, its specific impact as a poor prognostic predictor for BC patients with brain metastasis opens new avenues to target VGF to control the progression of brain metastatic disease. © 2024 The Pathological Society of Great Britain and Ireland.