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In this study, a novel series of histone deacetylases 6 (HDAC6) inhibitors containing polycyclic aromatic rings were discovered and evaluated for their pharmacological activities. The most potent compound 10c exhibited high HDAC6 inhibitory activity (IC50 = 261 nM) and excellent HDAC6 selectivity (SI = 109 for HDAC6 over HDAC3). 10c also showed decent antiproliferative activity in vitro with IC50 of 7.37–21.84 μM against four cancer cell lines, comparable to that of tubastatin A (average IC50 = 6.10 μM). Further mechanism studies revealed that 10c efficiently induced apoptosis and S-phase arrest in B16-F10 cells. In addition, 10c markedly increased the expression of acetylated-α-tubulin both in vitro and in vivo, without affecting the levels of acetylated-H3 (marker of HDAC1 inhibition). Furthermore, 10c (80 mg/kg) exhibited moderate antitumor efficacy in a melanoma tumour model with a tumour growth inhibition (TGI) of 32.9%, comparable to that (TGI = 31.3%) of tubastatin A. Importantly, the combination of 10c with NP19 (a small molecule PD-L1 inhibitor discovered by us before) decreased tumour burden substantially (TGI% = 60.1%) as compared to monotherapy groups. Moreover, the combination of 10c with NP19 enhanced the anti-tumour immune response, mediated by a decrease of PD-L1 expression levels and increased infiltration of anti-tumour CD8+ T cells in tumour tissues. Collectively, 10c represents a novel HDAC6 inhibitor deserving further investigation as a potential anti-cancer agent.

Abstract Background Prognostic index for survival estimation by clinical-demographic variables were previously proposed in chronic lymphocytic leukemia (CLL) patients. Our objective was to test in a large retrospective cohort of CLL patients the prognostic power of biological and clinical-demographic variable in a comprehensive multivariate model. A new prognostic index was proposed. Methods Overall survival and time to treatment in 620 untreated CLL patients were analyzed retrospectively to evaluate the multivariate independence and predictive power of mutational status of immunoglobulin heavy chain variable gene segments (IGHV), high-risk chromosomal aberration such as 17p or 11q deletions, CD38 and ZAP-70 expression, age, gender, Binet stage, β2-microglobulin levels, absolute lymphocyte count and number of lymph node regions. Results IGHV mutational status and 17p deletion were the sole biological variables with independent prognostic relevance in a multivariate model for overall survival, which included easily measurable clinical parameters (Binet staging, β2-microglobulin levels) and demographics (age and gender). Analysis of time to treatment in Binet A patients below 70 years of age showed that IGHV was the most important predictor. A novel 6-variable clinical-biological prognostic index was developed and internally validated, which assigned 3 points for Binet C stage, 2 points/each for Binet B stage and for age > 65 years, 1 point/each for male gender, high β2-microglobulin levels, presence of an unmutated IGHV gene status or 17p deletion. Patients were classified at low-risk (score = 0-1; 21%), intermediate-risk (score 2-5; 63% of cases), high-risk (score 6-9; 16% of cases). Projected 5-year overall survival was 98%, 90% and 58% in low-, intermediate- and high-risk groups, respectively. A nomogram for individual patient survival estimation was also proposed. Conclusions Data indicate that IGHV mutational status and 17p deletion may be integrated with clinical-demographic variables in new prognostic tools to estimate overall survival.

Abstract Background ZAP-70 is an independent negative prognostic marker in chronic lymphocytic leukemia (CLL). Usually, its expression is investigated by flow cytometric protocols in which the percentage of ZAP-70 positive CLL cells is determined in respect to isotypic control (ISO-method) or residual ZAP-70 positive T cells (T-method). These methods, however, beside suffering of an inherent subjectivity in their application, may give discordant results in some cases. The aim of this study was to assess the prognostic significance of these methods in comparison with another in which ZAP-70 expression was evaluated as a Mean-Fluorescence-Intensity Ratio between gated T and CLL cells (T/B Ratio-method). Methods Cytometric files relative to ZAP-70 determination according to the three readouts were retrospectively reviewed on a cohort of 173 patients (test set), all with complete clinical and biological prognostic assessment and time-to-treatment (TTT) available. Findings were then validated in an independent cohort of 341 cases from a different institution (validation set). Results The optimal prognostic cut-offs for ZAP-70 expression were selected at 11% (ISO-method) or 20% of positive cells (T-method), as well as at 3.0 (T/B Ratio-method) in the test set; these cut-offs yielded 66, 60 and 73 ZAP-70+ cases, respectively. Univariate analyses resulted in a better separation of ZAP-70+ vs. ZAP-70- CLL patients utilizing the T/B Ratio, compared to T- or ISO-methods. In multivariate analyses which included the major clinical and biological prognostic markers for CLL, the prognostic impact of ZAP-70 appeared stronger when the T/B-Ratio method was applied. These findings were confirmed in the validation set, in which ZAP-70 expression, evaluated by the T- (cut-off = 20%) or T/B Ratio- (cut-off = 3.0) methods, yielded 180 or 127 ZAP-70+ cases, respectively. ZAP-70+ patients according to the T/B Ratio-method had shorter TTT, both if compared to ZAP-70- CLL, and to cases classified ZAP-70+ by the T-method only. Conclusions We suggest to evaluate ZAP-70 expression in routine settings using the T/B Ratio-method, given the operator and laboratory independent feature of this approach. We propose the 3.0 T/B Ratio value as optimal cut-off to discriminate ZAP-70+ (T/B Ratio less than 3.0) from ZAP-70- (T/B Ratio more/equal than 3.0) cases.

Abstract Studies of gene expression profiling have been successfully used for the identification of molecules to be employed as potential prognosticators. In analogy with gene expression profiling, we have recently proposed a novel method to identify the immunophenotypic signature of B-cell chronic lymphocytic leukemia subsets with different prognosis, named surface-antigen expression profiling. According to this approach, surface marker expression data can be analysed by data mining tools identical to those employed in gene expression profiling studies, including unsupervised and supervised algorithms, with the aim of identifying the immunophenotypic signature of B-cell chronic lymphocytic leukemia subsets with different prognosis. Here we provide an overview of the overall strategy employed for the development of such an "outcome class-predictor" based on surface-antigen expression signatures. In addition, we will also discuss how to transfer the obtained information into the routine clinical practice by providing a flow-chart indicating how to select the most relevant antigens and build-up a prognostic scoring system by weighing each antigen according to its predictive power. Although referred to B-cell chronic lymphocytic leukemia, the methodology discussed here can be also useful in the study of diseases other than B-cell chronic lymphocytic leukemia, when the purpose is to identify novel prognostic determinants.

Working from home and work flexibility have been highly researched academic topics over the past forty years, and their importance was further amplified during the COVID-19 pandemic. Numerous qualitative and quantitative studies were aimed at better understanding this work arrangement, but they often encountered the challenges of limited scope and the inability to generalize their results. The goal of this study was to test the consistency of the instrument used in measuring the experiences of working from home for Croatian engineers, check the presence of its latent dimensions, and finally determine whether these dimensions could predict engineers’ job satisfaction. Three factors were extracted by exploratory factor analysis (productivity and work quality, work-life balance, and organizations’ distrust and control), while the multiple linear regression analysis ran on those factors as predictors proved that, although work-life balance does not influence job satisfaction, productivity and work quality positively predict it, while organizations’ distrust and control do so negatively.

Collaboration between researchers is seen as paramount in advancing science, be it because of its potential to offer novel ideas crossing scientific fields, because of its ability to boost productivity by having researchers who work well together, or by introducing and retaining new scientists to a wider network of peers, allowing them to access knowledge and information otherwise unavailable. This article sets to explore a specific part of scientific collaboration: mentor-protégés collaboration, especially during the formative years of a protégé's scientific career, during the writing of their dissertation and five years after. Gathering data on scientific productivity from the publication repository aggregator Croatian Scientific Bibliography, mentor-protégé collaboration was explored in order to test whether mentor's productivity could affect his or her protégé's productivity. Analysis of variance and linear regression analysis confirm that mentor productivity is positively correlated with protégé productivity, especially in the case where mentors are highly productive (stars) scientists. Additionally, network values such as betweenness and weighted degree centralities are explored in order to test whether mentors' values will affect protégé's position in the network. While mentor-protégé betweenness centrality values are found not to be correlated, weighted degree measures do seem to play an important role in introducing protégés to their mentor's network of peers and co-authors.

Este trabalho objetiva analisar algumas ações desenvolvidas pelo Napne (Núcleo de Atendimento a Pessoas com Necessidades Específicas) referentes ao trabalho docente realizado pelo atendimento educacional especializado com um estudante no contexto da educação profissional e tecnológica. O referido aluno apresenta deficiência física decorrente de uma encefalopatia crônica não degenerativa, também conhecida como paralisia cerebral, que ocorreu durante seu nascimento. As ações executadas ancoram-se na perspectiva histórico-cultural de Vigotski e na pedagogia histórico-crítica de Saviani. Para tanto, adotou-se como procedimento metodológico um estudo de caso baseado nas principais ações executadas no período letivo compreendido entre 2018 e 2019. Destacou-se neste estudo o desenvolvimento de estratégias de ensino-aprendizagem baseadas no atendimento educacional especializado e no trabalho colaborativo, no intuito de proporcionar avanços na aprendizagem do discente. A análise do trabalho desenvolvido evidenciou a importância do professor de Educação Especial para a efetivação de práticas inclusivas consistentes e adequadas aos estudantes com deficiência na educação profissional e tecnológica.

Objective: The aim of the study was to identify predictors of heart-focused anxiety in patients with heart failure. A better understanding of such predictors may help in detecting the comorbidity underlying heart-focused anxiety and identifying patients who need psychological help. Methods: In order to account for multiple sources of heart-focused anxiety, we included psychological, lifestyle, and medical/laboratory predictors. The study involved 148 patients, of whom 74 had a leading diagnosis of worsening heart failure and were hospitalized during the COVID-19 epidemic. A second group of 74 patients suffering from cardiovascular diseases without a diagnosis of acute heart failure, were examined in various out-patient cardiology clinics. The sample consisted of 37.8% females and 62.2% males, with an average age of 63.35 years. The patients completed the Cardiac Anxiety Questionnaire, the Generalized Anxiety Disorder scale, the Patient Health Questionnaire, and the Intolerance of Uncertainty Scale. Results: Patients with heart failure with higher levels of depression and intolerance of uncertainty had higher overall levels of heart-focused anxiety, higher levels of fear about chest and heart sensations. Older patients with higher levels of depression had higher levels of activity avoidance, especially activities believed to elicit cardiac symptoms. Cardiac patients with higher level of anxiety and with anaemia as comorbidity had higher levels of heart-focused attention and monitoring of cardiac activity. Conclusion: In patients with heart failure, the presence of heart-focused anxiety significantly reduces the quality of life, leads to avoidant behaviours, and is associated with anxiety and depressive symptoms. These patients are more likely to seek medical help and specialist services, but the need for psychological help is very rarely recognized.

This article takes on the task of exploring gig economy in its various forms and definitions, starting from its economic origins as a way to reduce transaction costs and overheads in firms making use of modern technology, and working up to some of its social consequences, such as the transforming of employees in just-in-time resources, fragmenting their labour and eroding their ability to organize and unionize in order to better defend their rights. Focussing on the influence platforms have on their users, be it in the role of workers or customers, it questions their far-reaching impacts on society and economy in terms of their positive, neutral or negative consequences for workers, as most of the literature agrees on the heavily skewed positive consequences for businesses. In order to make sense of existing research made on "giggers" this article tries to provide a scope of the gig economy using, which has been difficult to achieve as numerous researchers, institutions, and even states, define gig economy in different ways, with their data varying depending on definitions, dates, and methodological approaches. Finally, the article explores three distinct "selling points" of gig economy, namely: the possibility to generate (not always) steady income, the flexibility it offers to its users, and its consequences on workers' social and emotional state, putting into question their benefits for workers, for the profit of platforms and businesses.

Abstract The aim was to compare short-term results of transvaginal hybrid-NOTES (NSR) with traditional laparoscopic technique in sigmoid resection (LSR) in cases of diverticulitis. Natural Orifice Transluminal Endoscopic Surgery has been evolved as a minimally invasive procedure to reduce the operative trauma due to the absence of specimen extraction through the abdominal wall causing less postoperative pain, and shorter hospital stay. Despite the increasing use and published case series of NSR for diverticulitis as a laparoscopic procedure with transvaginal stapling and specimen extraction, there are no studies comparing this procedure with LSR. Twenty NSR patients operated at the Cologne-Merheim Medical Center have been documented and compared with 20 female LSR patients matched for body mass index, American Society of Anesthesiologists-classification (ASA), Hansen/Stock classification, and age. To ensure comparability regarding peri- and postoperative care, only procedures performed by the same surgeon were included. Procedural time, intra- and postoperative complications, conversion rate, postoperative pain, the duration of an epidural catheter, analgesic consumption, and postoperative length of hospital stay were analyzed. There were no significant differences in the sum of pain levels (p = 0.930), length of procedure (p = 0.079), intra- and postoperative complications, as well as duration of an epidural catheter. On the contrary, there were significant positive effects for NSR on morphine requirement at day seven and eight (p = 0.019 and p = 0.035 respectively) as well as the postoperative length of hospital stay (p = 0.031). This retrospective study reveals significant positive effects for NSR compared to LSR regarding length of hospital stay as well as morphine consumption after removal of the epidural catheter, whereas there were no significant differences in complication rate and procedural time. In summary, NSR is an adequate alternative to traditional laparoscopic sigmoid resection considering the surgeons experience and the patient’s personal preferences.

Background and study aims Endoscopic treatment has markedly improved the high morbidity and mortality in patients with upper gastrointestinal tract leakage. Most procedures employ either covered self-expanding metal stents (SEMS) or endoscopic vacuum therapy (EVT), both with good clinical success but also with concomitant significant shortcomings inherent in each technique. A newly developed device, the VACStent, combines the fully covered SEMS with a polyurethane sponge cylinder anchored on the outside. This allows endoluminal EVT while keeping the intestinal lumen patent. The benefit is prevention of stent migration because the suction force of the sponge-cylinder immobilizes the VACStent on the intestinal wall, while at the same time, the attached external vacuum pump suctions off any secretions and improves healing with negative-pressure wound treatment (NPWT). Patients and methods In this pilot study, the first patients to receive the VACStent were assessed. Outcomes included the applicability and stability of the VACStent system together with the clinical course. Results Three patients with different clinical courses were managed with the VACStent. The first patient suffered anastomotic leakage following subtotal esophagectomy and was successfully treated with two postoperative VACStents for 12 days. The second patient received a covered SEMS for 14 days for acute Boerhaave syndrome. Due to persistent leakage, management was converted to EVT. Seven days, later a VACStent was inserted to allow oral nutrition while the leak finally closed. In the third patient, a LINX Reflux Management System had to be removed for erosion, leaving the gastroesophageal junction (GEJ) with a full-thickness gap. After VACstent insertion, successful closure was achieved within 4 days. Conclusions These clinical cases demonstrate the applicability and efficacy of the VACstent in management of esophageal and anastomotic leakage. With its vacuum sponge, the stent fosters wound healing while the covered SEMS keeps the passage patent for nutrition.

Different actors, or stakeholders, are interested and want to participate in discussions and interventions related to the topic of skills as an important outcome of engineering education. In the Croatian context, the entire process is still predominantly internally driven and determined by academic evaluations while the involvement of the alumni and employers as external stakeholders is sporadic and under researched. Since Croatian employers are not sufficiently familiar with the levels and structures of reformed study programs, the main objective of this research was to assess to what extent the current and largely accepted set of engineering skills fit their expectations. By reviewing available literature, 36 key skills were identified and used in a questionnaire administrated to Croatian employers, resulting in 418 completed and usable responses. Results show that employers find every assessed skill as somewhat/extremely valuable. However, it is found that employers most valued skills related to the wider set of transferable skills with somewhat greater emphases on skills that reflect professionalism and work ethic. In general, it turned out that employers approach transferable skills in terms of their functionality. Mean comparison within subgroups has shown statistically significant differences with regard to respondent’s gender. In general, women fit the theorized dimensions more than their male counterparts, perhaps indicating that they understand all skills, and transferable skills in particular, more holistically than men. Finally, in order to understand the underlying structure of the explored items, exploratory factor analysis was employed, resulting in 8 clear dimensions suggesting engineering “employability skills” in the Croatian context.

The aim of this study is to elucidate the effects of weathering on wood coatings for exterior use. By means of analytical techniques as DSC, DMA, tensile test, UV/Vis and FTIR-ATR spectroscopies, it is possible to identify and measure the degree of damage, and so the chemical, physical and mechanical changes caused by degradation phenomena. The results can improve the predictive capability on coatings' performance (glass transition, elasticity, light transmission) and help the assessment of the protective ability of light-stabilizing additives, in order to satisfy the requirements of coating producers and users.