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Cancer: Key proteins hiding in the neighbourhood Cancer is considered a systems disease in which the interactors of cancer-related proteins have a key role, also as targets to fight cancer. New therapeutic approaches are needed to improve success rates and to identify suitable proteins as novel, alternative drug targets. We designed a computational approach, combining mutation and differential expression data with network information, to analyse the interactions of cancer-related proteins in colon, breast, liver and lung cancer. We found that first (direct) neighbours, not linked previously to the given cancer type, are similarly important as mutated proteins known to be involved in cancer development. We found 223 drugs already in the clinic targeting these proteins but not yet used against cancer as their oncology relevance was hidden so far. Our observations open up new strategies for target selection and anti-cancer drug discovery.

Recent findings show that single, non-neuronal cells are also able to learn signalling responses developing cellular memory. In cellular learning nodes of signalling networks strengthen their interactions e.g. by the conformational memory of intrinsically disordered proteins, protein translocation, miRNAs, lncRNAs, chromatin memory and signalling cascades. This can be described by a generalized, unicellular Hebbian learning process, where those signalling connections, which participate in learning, become stronger. Here we review those scenarios, where cellular signalling is not only repeated in a few times (when learning occurs), but becomes too frequent, too large, or too complex and overloads the cell. This leads to desensitisation of signalling networks by decoupling signalling components, receptor internalization, and consequent downregulation. These molecular processes are examples of anti-Hebbian learning and ‘forgetting’ of signalling networks. Stress can be perceived as signalling overload inducing the desensitisation of signalling pathways. Ageing occurs by the summative effects of cumulative stress downregulating signalling. We propose that cellular learning desensitisation, stress and ageing may be placed along the same axis of more and more intensive (prolonged or repeated) signalling. We discuss how cells might discriminate between repeated and unexpected signals, and highlight the Hebbian and anti-Hebbian mechanisms behind the fold-change detection in the NF-κB signalling pathway. We list drug design methods using Hebbian learning (such as chemically-induced proximity) and clinical treatment modalities inducing (cancer, drug allergies) desensitisation or avoiding drug-induced desensitisation. A better discrimination between cellular learning, desensitisation and stress may open novel directions in drug design, e.g. helping to overcome drug resistance. [ABSTRACT FROM AUTHOR]

To assess the efficacy of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) for treatment of nonalcoholic fatty liver disease (NAFLD) or steatohepatitis (NASH), we performed a systematic review and meta-analysis of randomized controlled trials (RCTs). Three large electronic databases were systematically searched (up to 15 December 2020) to identify placebo-controlled or active-controlled RCTs using different GLP-1 RAs. We included eleven placebo-controlled or active-controlled phase-2 RCTs (involving a total of 936 middle-aged individuals) that used liraglutide (n = 6 RCTs), exenatide (n = 3 RCTs), dulaglutide (n = 1 RCT) or semaglutide (n = 1 RCT) to specifically treat NAFLD or NASH, detected by liver biopsy (n = 2 RCTs) or imaging techniques (n = 9 RCTs). Compared to placebo or reference therapy, treatment with GLP-1 RAs for a median of 26 weeks was associated with significant reductions in the absolute percentage of liver fat content on magnetic resonance-based techniques (pooled weighted mean difference: −3.92%, 95% confidence intervals (CI) −6.27% to −1.56%) and serum liver enzyme levels, as well as with greater histological resolution of NASH without worsening of liver fibrosis (pooled random-effects odds ratio 4.06, 95% CI 2.52–6.55; for liraglutide and semaglutide only). In conclusion, treatment with GLP-1 RAs (mostly liraglutide and semaglutide) is a promising treatment option for NAFLD or NASH that warrants further investigation.

Recent randomized controlled trials (RCTs) tested the efficacy of sodium-glucose cotransporter-2 (SGLT-2) inhibitors to specifically treat nonalcoholic fatty liver disease (NAFLD). We systematically searched three electronic databases (up to 31 October 2020) for identifying placebo-controlled or head-to-head RCTs that used SGLT-2 inhibitors for treatment of NAFLD. No published RCTs with paired liver biopsy data were available for the meta-analysis. Primary outcome measures were changes in serum liver enzyme levels and liver fat content on imaging techniques. Overall, we included a total of twelve RCTs testing the efficacy of dapagliflozin (n = six RCTs), empagliflozin (n = three RCTs), ipragliflozin (n = two RCTs) or canagliflozin (n = one RCT) to specifically treat NAFLD for a median period of 24 weeks with aggregate data on 850 middle-aged overweight or obese individuals with NAFLD (90% with type 2 diabetes). Compared to placebo/reference therapy, treatment with SGLT-2 inhibitors significantly decreased serum alanine aminotransferase (weighted mean differences (WMD): −10.0 IU/L, 95%CI −12.2 to −7.79 IU/L; I2 = 10.5%) and gamma-glutamyltransferase levels (WMD: −14.49 IU/L, 95%CI −19.35 to −9.63 IU/L, I2 = 38.7%), as well as the absolute percentage of liver fat content on magnetic resonance-based techniques (WMD: −2.05%, 95%CI −2.61 to −1.48%; I2 = 0%). In conclusion, SGLT-2 inhibitors seem to be a promising treatment option for NAFLD.

In 2006 a novel approach to talent support was promoted by several talent support programmes in Hungary. The new idea was a network approach. The nationwide network of so-called TalentPoints and its framework, the Hungarian Genius Program, gained substantial European Union funding in 2009, and today it is growing rapidly. A novel concept of talent is also used by the programme: it perceives everyone as potentially gifted. The Hungarian Genius Program organizes the festive events of Talent Days on regional, national and European levels, sets up Talent Support Councils and has introduced the Talent Loan programme. (Contains 2 figures.)

Aim: To evaluate the relationship of genetic variability of adiponectin (ADIPOQ), leptin (LEP) and leptin receptor (LEPR) genes with glucose‐insulin system and markers of subclinical atherosclerosis (ATS) in patients with newly diagnosed type 2 diabetes. Materials and methods: In 794 subjects we performed: 1) euglycemic hyperinsulinemic clamp to assess insulin sensitivity; 2) mathematical modelling of a 5h‐OGTT to estimate β‐cell function; 3) resting ECG; 4) carotid artery and lower limb artery eco‐doppler sonography to identify ATS; 5) genotyping of tag‐SNPs within ADIPOQ, LEP and LEPR gene. Results: Regression analyses showed: 1) adiponectin levels were negatively associated with BMI, waist‐to‐hip ratio and triglycerides and positively with HDL and insulin sensitivity (p‐all<0.03); 2) leptin levels were positively associated with BMI, HDL‐cholesterol and plasma triglycerides and negatively with insulin sensitivity (p‐all<0.001). Two SNPs (rs1501299 and rs2241767) within ADIPOQ gene were associated with circulating levels of adiponectin. The ADIPOQ‐GAACA haplotype was associated with plasma adiponectin (p=0.034; β=‐0.24), ECG abnormalities (p=0.012; OR=2.76), carotid ATS (p=0.025; OR=2.00) and peripheral limb artery ATS (p=0.032; OR=1.90). The LEP‐CTA haplotype showed an association with ischemic ECG abnormalities (p=0.017; OR=2.24). Finally, LEPR‐GAACGG was associated with circulating leptin (p=0.005; β=‐0.31) and worst β‐cell function (p=0.023; β=‐15.10). Omnibus haplotype analysis showed that ADIPOQ haplotypes were associated with levels of adiponectin and common carotid artery ATS, LEP with peripheral limb artery ATS, whereas LEPR haplotypes influenced circulating levels of leptin. Conclusions: Results of this study reinforce knowledge on adipokines' role in regulating glucose metabolism; in particular highlighted the potential atherogenic role of leptin and the anti atherogenic role of adiponectin. [ABSTRACT FROM AUTHOR]

The first six years of a new program to organize high-level scientific research training for gifted high school students in Hungary are described. Besides giving top-level research opportunities for talented students in their most receptive age, the program has already helped the establishment of almost two hundred scientific research clubs. (Contains 4 references.) (Author/CR)