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Somatic copy number alterations play a critical role in oncogenesis. Loss of chromosomal regions containing tumor suppressors can lead to collateral deletion of passenger genes. This can be exploited therapeutically if synthetic lethal partners of such passenger genes are known and represent druggable targets. Here, we report that VPS4B gene, encoding an ATPase involved in ESCRT‐dependent membrane remodeling, is such a passenger gene frequently deleted in many cancer types, notably in colorectal cancer (CRC). We observed downregulation of VPS4B mRNA and protein levels from CRC patient samples. We identified VPS4A paralog as a synthetic lethal interactor for VPS4B in vitro and in mouse xenografts. Depleting both proteins profoundly altered the cellular transcriptome and induced cell death accompanied by the release of immunomodulatory molecules that mediate inflammatory and anti‐tumor responses. Our results identify a pair of novel druggable targets for personalized oncology and provide a rationale to develop VPS4 inhibitors for precision therapy of VPS4B‐deficient cancers. Synopsis VPS4B and VPS4A paralogs are involved in the remodeling of biological membranes, a critical step for many intracellular processes. This study highlights the possibility of using synthetic lethality between these paralogs for treatment of VPS4B‐deficient cancers. VPS4B protein abundance was decreased in colorectal cancer (CRC) patient samples. A synthetic lethal phenotype was generated by simultaneous depletion of VPS4A and B in various CRC cell lines grown in vitro and in vivo . Synthetic lethality between VPS4A and B was independent of other oncogenic mutations, and conserved between human and mouse, thus of high penetrance. Simultaneous depletion of VPS4A and B caused pleiotropic effects e.g. inhibited endocytosis and cell cycle progression, and induced a stress‐associated sterile inflammatory response. DAMPs and other immunomodulatory molecules released by VPS4A+B‐depleted dying cells may favor the induction of anti‐tumor innate and adaptive immune responses. Graphical Abstract VPS4B and VPS4A paralogs are involved in the remodeling of biological membranes, a critical step for many intracellular processes. This study highlights the possibility of using synthetic lethality between these paralogs for treatment of VPS4B‐deficient cancers.

TNF-related apoptosis-inducing ligand (TRAIL) is a type II transmembrane protein capable of selectively inducing apoptosis in cancer cells by binding to its cognate receptors. Here, we examined the anticancer efficacy of a recently developed chimeric AD-O51.4 protein, a TRAIL fused to the VEGFA-originating peptide. We tested AD-O51.4 protein activity against human colorectal cancer (CRC) models and investigated the resistance mechanism in the non-responsive CRC models. The quantitative comparison of apoptotic activity between AD-O51.4 and the native TRAIL in nine human colorectal cancer cell lines revealed dose-dependent toxicity in seven of them; the immunofluorescence-captured receptor abundance correlated with the extent of apoptosis. AD-O51.4 reduced the growth of CRC patient-derived xenografts (PDXs) with good efficacy. Cell lines that acquired AD-O51.4 resistance showed a significant decrease in surface TRAIL receptor expression and apoptosis-related proteins, including Caspase-8, HSP60, and p53. These results demonstrate the effectiveness of AD-O51.4 protein in CRC preclinical models and identify the potential mechanism underlying acquired resistance. Progression of AD-O51.4 to clinical trials is expected.

Burkitt lymphoma (BL) is a rapidly growing tumor, characterized by high anabolic requirements. The MYC oncogene plays a central role in the pathogenesis of this malignancy, controlling genes involved in apoptosis, proliferation, and cellular metabolism. Serine biosynthesis pathway (SBP) couples glycolysis to folate and methionine cycles, supporting biosynthesis of certain amino acids, nucleotides, glutathione, and a methyl group donor, S-adenosylmethionine (SAM). We report that BLs overexpress SBP enzymes, phosphoglycerate dehydrogenase (PHGDH) and phosphoserine aminotransferase 1 (PSAT1). Both genes are controlled by the MYC-dependent ATF4 transcription factor. Genetic ablation of PHGDH/PSAT1 or chemical PHGDH inhibition with NCT-503 decreased BL cell lines proliferation and clonogenicity. NCT-503 reduced glutathione level, increased reactive oxygen species abundance, and induced apoptosis. Consistent with the role of SAM as a methyl donor, NCT-503 decreased DNA and histone methylation, and led to the re-expression of ID4, KLF4, CDKN2B and TXNIP tumor suppressors. High H3K27me3 level is known to repress the MYC negative regulator miR-494. NCT-503 decreased H3K27me3 abundance, increased the miR-494 level, and reduced the expression of MYC and MYC-dependent histone methyltransferase, EZH2. Surprisingly, chemical/genetic disruption of SBP did not delay BL and breast cancer xenografts growth, suggesting the existence of mechanisms compensating the PHGDH/PSAT1 absence in vivo.

Colorectal cancer (CRC) is the second most common cancer in Europe and a leading cause of death worldwide. Patient-derived xenograft (PDX) models maintain complex intratumoral biology and heterogeneity and therefore remain the platform of choice for translational drug discovery. In this study, we implanted 37 primary CRC tumors and five CRC cell lines into NU/J mice to develop xenograft models. Primary tumors and established xenografts were histologically assessed and surveyed for genetic variants and gene expression using a panel of 409 cancer-related genes and RNA-seq, respectively. More than half of CRC tumors (20 out of 37, 54%) developed into a PDX. Histological assessment confirmed that PDX grading, stromal components, inflammation, and budding were consistent with those of the primary tumors. DNA sequencing identified an average of 0.14 variants per gene per sample. The percentage of mutated variants in PDXs increased with successive passages, indicating a decrease in clonal heterogeneity. Gene Ontology analyses of 4180 differentially expressed transcripts (adj. p value < 0.05) revealed overrepresentation of genes involved in cell division and catabolic processes among the transcripts upregulated in PDXs; downregulated transcripts were associated with GO terms related to extracellular matrix organization, immune responses, and angiogenesis. Neither a transcriptome-based consensus molecular subtype (CMS) classifier nor three other predictors reliably matched PDX molecular subtypes with those of the primary tumors. In sum, both genetic and transcriptomic profiles differed between donor tumors and PDXs, likely as a consequence of subclonal evolution at the early phase of xenograft development, making molecular stratification of PDXs challenging.

Somatic copy number alterations play a critical role in oncogenesis. Loss of chromosomal regions containing tumor suppressors can lead to collateral deletion of passenger genes. This can be exploited therapeutically if synthetic lethal partners of such passenger genes are known and represent druggable targets. Here, we report that VPS4B gene, encoding an ATPase involved in ESCRT‐dependent membrane remodeling, is such a passenger gene frequently deleted in many cancer types, notably in colorectal cancer (CRC). We observed downregulation of VPS4B mRNA and protein levels from CRC patient samples. We identified VPS4A paralog as a synthetic lethal interactor for VPS4B in vitro and in mouse xenografts. Depleting both proteins profoundly altered the cellular transcriptome and induced cell death accompanied by the release of immunomodulatory molecules that mediate inflammatory and anti‐tumor responses. Our results identify a pair of novel druggable targets for personalized oncology and provide a rationale to develop VPS4 inhibitors for precision therapy of VPS4B‐deficient cancers.

Taking into account the evolution of the Common Agricultural Policy (CAP), it is wondered to what extent the “green” transformation of this policy and the accompanying change in the distribution of direct payments between farms contributed to the elimination of disproportions in agricultural income. The aim of the study was to investigate the changes in the proclaimed concepts related to the development of the EU agricultural sector in terms of their “green” transformation, and to assess the impact of “green” CAP payments on income inequalities between farms. The research was conducted based on the data representative for Polish commercial farms for the years 2004–2019, covering three financial perspectives of the agricultural policy. The methods of counterfactual modelling and assessment of income inequality were used in the study. The analyses showed that the evolution of the CAP priorities, and hence instruments, towards the pro-environmental (or, more broadly, towards sustainability) have so far had a rather negative impact on the income of Polish farms. In its current form, the support dedicated to environmental and climate protection did not fully compensate farmers for income losses resulting from the use of pro-environmental agricultural practices. Moreover, “green” CAP payments did not play a significant role in shaping income inequalities. Therefore, we can conclude that the CAP instruments do not contribute sufficiently to sustainable development (economic, social, and environmental), because they do not support/motivate farmers to change their production standards.

Despite research conducted worldwide, there is no treatment specifically targeting SARS-CoV-2 infection with efficacy proven by randomized controlled trials. A chance for a breakthrough is vaccinating most of the global population. Public opinion surveys on vaccine hesitancy prompted our team to investigate Polish healthcare workers’ (HCWs) attitudes towards the SARS-CoV-2 and influenza vaccinations. In-person and online surveys of HCWs: doctors, nurses, medical students, and other allied health professionals (n = 419) were conducted between 14 September 2020 and 5 November 2020. In our study, 68.7% of respondents would like to be vaccinated against COVID-19. The safety and efficacy of COVID-19 vaccinations would persuade 86.3% of hesitant and those who would refuse to be vaccinated. 3.1% of all respondents claimed that no argument would convince them to get vaccinated. 61.6% of respondents declared a willingness to receive an influenza vaccination, of which 83.3% were also inclined to receive COVID-19 vaccinations. Although most respondents—62.5% (262/419) indicated they trusted in the influenza vaccine more, more respondents intended to get vaccinated against COVID-19 in the 2020/2021 season. The study is limited by its nonrandom sample of HCWs but provides a preliminary description of attitudes towards SARS-CoV-2 vaccination.

The study aimed to examine the changes in income inequalities in Polish farms and the impact of introducing the threshold of direct payments for farms (EUR 60 000) to form these inequalities. The research was based on data from the Farm Accountancy Data Network (FADN) for the years: 2006, 2013 and 2018. In each year, the sample included at least 10 000 observations that represented over 700 000 farms. The results were verified using statistical tests relating to the comparisons of averages and distributions of farm income for two samples and the Gini coefficient. The study noted deepening income inequalities in Polish farms, as evidenced by the increasing value of the Gini coefficient in the subsequent years and the growing share of payments in the formation of these inequalities. Neither for the sample analysed nor the field of observation of farms will introduce the threshold for direct payments per farm of at least EUR 60 000 (including labour costs) change the polarisation of income.

Introduction:Malnutrition is highly prevalent in cancer patients, significantly influencing their clinical outcomes and prognosis. The study was conducted to investigate the association between inflammatory biomarkers, nutritional status and progression of the disease across various types of cancers.Material and methods:Retrospective data from 200 consecutive Caucasian cancer patients admitted to a major oncology hospital for cancer treatment were analyzed according to age, sex, cancer type, nutritional status (percentage body weight loss – %BWL), body mass index (BMI), percentage of dietary intake from the calculated requirement for nutrients (%DI)), and laboratory results (albumin levels, total protein concentration, C-reactive protein – CRP). Inflammatory biomarkers such as prognostic nutritional index (PNI), neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR) were assessed.Results:Prognostic nutritional index (ρ = –0.464, p < 0.001), PLR (ρ = 0.293, p = 0.019), albumin level (ρ = –0.490, p < 0.001), platelet count (ρ = 0.114, p = 0.370), neutrophil count (ρ = 0.273, p = 0.030), CRP (ρ = 0.293, p = 0.019) and lymphocyte count (ρ = –0.288, p = 0.021) were significantly associated with %BWL. No significant association was found with NLR. Cancer dissemination was significantly associated with PNI (OR: 0.93, 95% CI: 0.88–0.98), PLR (OR: 1.00, 95% CI: 1.00–1.01), albumin (OR: 0.86, 95% CI: 0.80–0.93), platelet count (OR: 1.01, 95% CI: 1.00–1.01), %BWL (OR: 1.06, 95% CI: 1.02–1.10) and %DI (OR: 0.97, 95% CI: 0.96–0.99) but not with NLR, total protein level, total lymphocyte count, or BMI. For patients with albumin levels below 35 g/l, the likelihood of disseminated cancer was more than five times higher (OR: 5.45, 95% CI: 2.05–14.48).Conclusions:The intensity of inflammation may be responsible for the severity of malnutrition and cancer prognosis.

Background: Poland is facing the growing problem of overweight and obesity in the population, which makes it necessary to conduct a thorough assessment of the existing food environment policies. The aims of the study were: (1) to depict the strength of healthy food environment policies in Poland and identify implementation policies and infrastructure support gaps; (2) to identify and prioritise improvement policies, taking into account their importance, achievability and equity. Methods: We used the Healthy Food Environment Policy Index (Food-EPI). An experts’ panel rated Polish policies and infrastructure compared to international best practices and developed a list of recommended improvement actions addressing both components. Results: eight of the twenty-two policy and four of the twenty-two infrastructure indicators achieved the “no/very weak policy” result. Another four policy and five infrastructure indicators were considered “weak”. Another seven and eight indicators, respectively, were assessed as “moderate”. Among the identified actions, the highest priority was given to a food labelling system and training for persons involved in nutrition in schools. Conclusions: The Polish healthy food environment has been assessed as very weak or weak in most aspects. The infrastructure was assessed as slightly better compared to the policies domain, with more indicators receiving the “moderate” score.