We have investigated the self-assembly of a strong dipolar molecule (LDipCC) on the semiconducting Si(111)-B surface with scanning tunneling microscopy (STM), density functional theory (DFT) calculations and STM simulations. Although the formation of an extended two-dimensional network was clearly revealed by STM under ultra-high vacuum, the assignment of a specific STM signature to the different terminal groups from the LDipCC molecular unit required a complete analysis by numerical simulations. The overall observed assembly is explained in terms of STM contrasts associated with the molecular structure of LDipCC and the molecule-surface interactions. To distinguish the relative arrangement of the dipolar molecules within the assembly, a rational combination of experimental results and electronic structure calculations allows us to identify a single adsorbed LDipCC phase in which the molecular dipoles are homogeneously arranged into a parallel fashion on the Si(111)-B surface.

Background: Clonal neoantigens are formed early in cancer evolution and have been identified as a subset of patient specific mutations that are associated with improved clinical benefit and represent great promise as targets for the next generation of T cell therapies. Developing T cell therapies that target multiple clonal neoantigens represents a unique personalized approach to treating solid cancer, as they are present on all cancer cells, minimizing the risk of tumour escape, and absent from healthy tissue, potentially eliminating off-target toxicities. Access to sequencing data from over 600 NSCLC patients enrolled in the UK TRACERx study has enabled the development of the Achilles PELEUSTM bioinformatic platform. By opening an ethically approved tissue collection study NCT03517917, enabling access to matched tumour and blood samples from patients with selected cancers, our clonal neoantigen reactive T cell (cNeT) manufacturing process and supply chain has been validated for use in clinical trials. Methods: Matched tumor and blood samples were procured at the time of routine surgery from ten patients (eight with newly diagnosed stage I-III NSCLC and two with metastatic melanoma) for at-scale GMP runs. Briefly, TIL were isolated from tumor fragments and immature dendritic cells (DCs) generated from whole blood, prior to cryopreservation as intermediate products. Patient-specific clonal neoantigens were predicted using our proprietary PELEUSTM bioinformatic platform, enabling the manufacture of synthetic peptide masterpools to be used for the enrichment of cNeT in the VELOSTM manufacturing process. Co-culture of pre-expanded TIL and patient DCs loaded with clonal neoantigen peptides drives the selective expansion of cNeT, eliminating the requirement for high non-physiological levels of IL-2. Results: Here we present the successful scaled GMP production of cNeT from both primary and metastatic tumors using the VELOSTM manufacturing process in ten patients. All final products met QC release criteria and were composed of both CD4+ and CD8+ T cells. Extensive characterization of T cell responses showed cNeT exhibited functional responses determined by cytokine secretion following re-challenge, and specificity in response to clonal neoantigen peptides. Peptide deconvolution of masterpools identified multiple single T cell clone reactivities to clonal neoantigens in the final product. Conclusions: The VELOSTM process incorporating the PELEUSTM bioinformatic platform for prediction of clonal neoantigens is a novel platform for generating personalized T cell products directed at multiple cancer clonal neoantigen targets and has the potential to be utilized across a variety of solid tumors. This study demonstrates the feasibility of generating cNeT for the treatment of both advanced NSCLC and recurrent or metastatic melanoma and supported the successful regulatory approval in two first-in-human studies (NCT04032847 and NCT03997474) which opened in the UK in 2019. Citation Format: Henrieta Fraser, Rebecca Pike, Sarah Thirkell, Asiya Arshad, Sam Jide-Banwo, Hollie Bartley, Evi Rologi, Michal Pruchniak, Shreenal Patel, Jennine Mootien, Jane Robertson, Andrew Craig, Max Salm, Katy Newton, Luke Goodsell, Fong Chan, Gareth Wilson, Stephen Frenk, Iraj Ali, Karl Peggs, Mark W. Lowdell, Lyra Del Rosio, Andrew Hayes, Samra Turajlic, Farah Islam, David Lawrence, Mariam Jamal-Hanjani, Martin D. Forster, Edward Samuel. The development of a personalized autologous clonal neoantigen T cell therapy for the treatment of solid cancer using the VELOSTM manufacturing platform generates highly potent and reactive CD8+ and CD4+ T cells for clinical use [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT054.

Adoptive transfer of tumor infiltrating lymphocytes (TIL) has generated objective clinical responses in patients with advanced metastatic cancers. Therapeutic exploitation of neoantigens as targets can potentially lead to safer and more effective treatment modalities with reduced toxicities. The Achilles Therapeutics trial NCT03517917 enabled the acquisition of matched tumor specimens and peripheral blood samples from patients undergoing routine surgery and facilitated the development of the proprietary VELOSTM manufacturing process, generating a personalized clonal neoantigen specific T cell product. An in-depth characterization of T cells expanded with the VELOSTM process was performed and compared to a standard TIL product. Samples were obtained from patients with primary NSCLC or metastatic melanoma. TIL were expanded from tumor fragments after dissection in the presence of IL-2. Peptide pools corresponding to the clonal mutations that were identified using the PELEUSTM bioinformatics platform were used to pulse dendritic cells (DC) generated from peripheral blood monocytes from each patient. Clonal neoantigen specific T cells (cNeT) were expanded using the VELOSTM process by co-culture of TIL with the peptide-pulsed autologous DC. As a comparison, TIL were expanded with a rapid expansion protocol (REP-TIL) in the presence of allogeneic feeders, anti-CD3 antibody and high-dose IL-2. Intracellular cytokine staining was performed following rechallenge with individual peptide pools encoding the clonal mutations. Single peptide reactivities were identified using ELISPOT and extended flow cytometric analysis of markers associated with T cell fitness or dysfunction was performed to phenotypically characterize the cNeT, TIL and REP-TIL. Analysis of the immune cell composition showed that cNeT, TIL and REP-TIL have similar CD3+ T cell content (median cNeT 90.2%, TIL 87.3%, REP-TIL 95%, n=6) and are composed of CD4+ and CD8+ T cells (median CD4:CD8 ratio- cNeT 11.1, TIL 2.03 and REP-TIL 4.7, n=6). cNeT showed superior clonal neoantigen specificity compared to TIL or REP-TIL. The proportion of CD3+ T cells responding to clonal neoantigen rechallenge was increased in cNeT (median 24.3%) compared to TIL (median 0.6%) and REP-TIL (median 1.8%) (n=5). The VELOSTM process incorporating the PELEUSTM platform for prediction of clonal neoantigens generates T cell products enriched for clonal neoantigen reactivities and superior phenotypic characteristics compared to conventional TIL. The VELOSTM process is currently being used to manufacture cNeT for two first-in-human studies including NSCLC and melanoma patients (NCT04032847, NCT03997474). Ethical approval: The samples for the study were collected under an ethically approved protocol (NCT03517917). Citation Format: Eleni Kotsiou, Tie Zheng Hou, Joseph Robinson, Sonal Varsani, Theres Oakes, Pablo D. Becker, Shreenal Patel, Jennine Mootien, Andrew Craig, Jane Robertson, Edward Samuel, James Reading, Lyra Del Rosario, Andrew Haynes, Samra Turajlic, Farah Islam, David Lawrence, Mariam Jamal-Hanjani, Martin Foster, Sergio A. Quezada, Katy Newton. Next generation clonal neoantigen targeting T cells, generated using the PELEUSTM bioinformatics platform and the VELOSTM manufacturing method show superior reactivity and phenotypic characteristics than classical TIL products [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 875.

Infection with the new corona virus (SARS-CoV-2) was first registered in December 2019 in China, and then later spread rapidly to the rest of the world. On December 31, 2019, the World Health Organization (WHO) informed the public for the first time about causes of pneumonnia of unknown origin, in the city of Wuhan (Hubei Province, China), in people who were epidemiologically linked to a seafood and wet animal whole sale local market in Wuhan. Coronavrus disease, called COVID-19 (Corona virus disease 2019), after China quickly spread to most countries in the wold, and the WHO on March 11, 2020 declared a pandmic with this virus. SARS-CoV-2, has a high level of sequential similarities to the SARS-CoV-1 and uses the same receptors when it enters the human body (angiotensin-converting enzyme 2/ACE2). COVID-19 is respiratry infection that is primarily transmitted via respiratry droplets. Typical symptoms of COVID-19 infection can be very moderate (infected can be even asymptomatic) to very severe, with severe respiratory symptoms (bilateral severe pneumonia), septic schock, and fatal outcome. Numeous unknows regarding the biological, epidemilogical adn clinical characteristics of COVID-19, still exist, and make it impossible to predict with certainty the further course of the current pandemic. COVID-19 is primarily a disease of the respiratory system, but SARS-CoV-2, in a number of patients also penetrates the CNS, and apparently could be responsible for fatal outcome in some cases. The entrry of the virus into the brain can lead to neurological and psychiatric manifestationss, which are not uncommon, including headache, paresthesia, myalgia, impaired consciousnessm, confusion or delirum and cerebrovascular diseases. SARS-CoV-2 positive individuals should be evaluated in a timely manner for neurological and psychiatic symptoms because tretament of infection-related neurological and psychiatric complications is an important factor in better prognosis of severe COVID-19 patients.From the current point of view, it seems that in COVID-19 survivors, in the coming years and decades, the inflammatory systemic process and/or the inflammatory process of the brain could trigger long-term mechanisms that generally lead to an increase of neurological and neurodegenerative disorders. Psychosocial consequences as well as consequences for mental health are also significant, both for the general population and especially for health workers of all profiles. COVID-19 pandemia is associtaed with negative psychosocial consequences, including depressive symptoms, anxiety, anger and stress, sleep disorders, simpotms of posttrauamtic stres disorder, social isolation, loneliness and stigmatization.

Presents case reports of two psychiatric patients who suddenly deteriorated and burned in a severe psychiatric condition due to the circumstances they faced due to the COVID-19 pandemic, which required urgent admission and intensive psychiatric treatment. In the first case report, pandemic and restrictive measures were the predisposing factors for suicide attempt of the patient who is the war veteran with diagnosed complex PTSD, while the precipitating factors for the suicide attempt were impaired physician-patient communication, fear of losing a job and existential issues. There is a need to raise awareness in society that rising unemployment is associated with an increased number of suicides, as well as responsible and balanced media coverage of the COVID-19 pandemic. In the second case report, our patient with bipolar disorder got into relapse of disease with psychotic symptoms during the pandemic of COVID-19 after changes the work structure and after she illegally visited her son who was self-isolated after returning to B&H from abroad, with no self-protected equipment. Overall, both case studies illustrate the psychological potential that the crisis caused by the COVID-19 pandemic has on at-risk groups of psychiatric patients. (PsycInfo Database Record (c) 2021 APA, all rights reserved)

: Understanding the role of religious communities in Croatia and Bosnia and Her-zegovina’s post-Communist societies is very important for grasping the nature and history of democratic development in these two countries. A close investigation reveals that the relationship between the political and religious elites is cruci-al, but also subject to change given the shifting nature of social developments. Three stages in this relationship can be observed. The first phase started with the collapse of Yugoslavia and Communism in 1991-1992 and lasted until the early 2000s. This was a formative stage for the new societies, and religion played a key role in the national homogenisation and construction of new identities. The second phase, which started in the early 2000s and lasted most of the decade, was a period of relative economic prosperity, with a weakening of the nationalist political elites’ sway, and consequently a weakening of the role of the religious organisations. The third phase, which started with the financial crisis of 2008 and is still ongoing, is marked by a renewed populist and rightist agenda in politics, which has also resulted in a strengthening of the public role of organised religion in both countries.

BACKGROUND Occurrence of symptoms of fear and depression among general population during the outbreak of COVID-19 seems to present an emerging problem worldwide. The aim of this study was to examine levels of fear and depressive symptoms in association with COVID-19 outbreak and to assess other contributing factors in the population of Bosnia and Herzegovina. SUBJECTS AND METHODS Link to an anonymous questionnaire, mainly based on The Fear of COVID-19 Scale (Ahorsu et al. 2020) and two-item and nine-item Patient Health Questionnaires (PHQs) (Maurer et al. 2018) (background information, fear assessment and information regarding depression) was distributed online to general population of Bosnia and Herzegovina. RESULTS Out of 1201 respondents, 217 (18.0%) reported experiencing fear and 341 (28.4%) reported having symptoms of depression during COVID-19 outbreak. The mean age of the subjects was 30.57±11.26. Being older (OR=1.044; 95% CI 1.031-1.057; p<0.001) and having moderate to severe depressive symptoms (OR=1.093; 95% CI 1.067-1.120; p<0.001) were independent significant predictors for developing fear; living in rural environment (OR=0.551; 95% Cl 0.325-0.935; p=0.0027) significantly decreased the risk of developing fear; being female (OR=1.750; 95% CI 1.242-2.466; p=0.001), unemployed (OR=1.557; 95% CI 1.040-2.330; p=0.032) or student (OR=1.943; 95% CI 1.450-2.604; p<0.001) were independent significant predictors for developing moderate to severe depressive symptoms in association with COVID-19. Mann Whitney U-test showed that being older was statistically associated with fear (p<0.001) and being younger was statistically associated with depressive symptoms (p<0.001). CONCLUSIONS In conclusion, based on our findings, fear and depressive symptoms in general population of Bosnia and Herzegovina during the outbreak of COVID-19 were present in 18.06% (fear) and 28.39% (depression) of subjects and it was statistically associated with age, gender, occupation, living environment and may present a secondary uprising problem connected to outbreak of COVID-19.

U rimskom pravu gotovo da i nemamo izvore koji pažnju posvećuju direktno tijelu umrle osobe. Tijelo kao takvo nije bilo zaštićeno. Pokojnik se štitio, prvenstveno, kroz zaštitu groba, koji je smatran stvari posvećenoj kultu pokojnika – diis manibus relictae. Unatoč tome, detaljnija analiza pravnih izvora jasno afirmira tezu o postojanju pravila iz sfere pogrebnog prava, kojima je regulirano konstituiranje određenih ograničenih prava u vezi s tijelom umrle osobe, a usko povezanih s odlučivanjem o načinu obavljanja pogreba, kremacije, prijenosa tijela, izgradnji nadgrobnog spomenika i slično. Autor smatra kako se ostvarivanje ovih prava u prvom redu vrši po volji umrlog, a u slučaju kada je nije iskazao, na vršenje se pozivaju bračni drug i nužni nasljednici. Nasljednici se pozivaju onim redom kojim bi ih i po rimskom pravu pozivali na nasljedstvo, neovisno o tome jesu li išta iz imovine umrlog naslijedili. Opstojnost predstavljene koncepcije ispitana je i u okviru kanonskog prava, ali i europskog prava u doba kodificiranja privatnog prava tijekom 19.. i na početku 20. stoljeća. Imajući u vidu da ne postoje jedinstveni stavovi o ovim pitanjima, autor posebnu pozornost posvećuje pravnoj kulturi Austrijskog građanskog zakonika, ostavljajući mogućnost da se pravne praznine riješe u duhu rimske pravne tradicije.

People suffering from hearing impairment often have difficulties participating in conversations in so-called cocktail party scenarios where multiple individuals are simultaneously talking. Although advanced algorithms exist to suppress background noise in these situations, a hearing device also needs information about which speaker a user actually aims to attend to. The voice of the correct (attended) speaker can then be enhanced through this information, and all other speakers can be treated as background noise. Recent neuroscientific advances have shown that it is possible to determine the focus of auditory attention through noninvasive neurorecording techniques, such as electroencephalography (EEG). Based on these insights, a multitude of auditory attention decoding (AAD) algorithms has been proposed, which could, combined with appropriate speaker separation algorithms and miniaturized EEG sensors, lead to so-called neurosteered hearing devices. In this article, we provide a broad review and a statistically grounded comparative study of EEG-based AAD algorithms and address the main signal processing challenges in this field.

Supplemental Digital Content is available in the text. Checkpoint inhibitors (CPIs) have demonstrated a heterogenous spectrum of response and disease progression that may not be fully captured by conventional response criteria, such as a limited degree of progression, known as oligoprogression, which could benefit from local treatment. We retrospectively analyzed data from all patients diagnosed with metastatic melanoma, who received CPI between January 2006 and March 2018 at Royal Marsden. We enrolled 36 patients who experienced progression in a maximum of 3 metastatic sites, after achieving disease control from therapy with CPI, and were radically treated with the locoregional approach. We carried out Kaplan-Meier analysis to obtain progression free-survival post-first oligoprogression (PFS-PO1), overall survival (OS) post-first oligoprogression, and OS estimates. The median time to oligoprogression from the start of CPI was 12 months. At a median follow-up of 34 months, the median PFS-PO1 was 32 months, with 50% of patients not progressed at the time of the data cutoff. The median OS-post-first oligoprogression was not reached. At a median follow-up of 52 months (from the first cycle of CPI), the median OS was not reached, with 75% of patients alive at the time of analysis. Univariate and multivariate analyses demonstrated that baseline American Joint Committee on Cancer stage IV M1a or M1b is associated with a longer PFS-PO1 compared with stage M1c or M1d. We observed that local therapy for oligoprogression after CPI can result in durable disease control, suggesting that locoregional treatment should be considered in patients being treated with immunotherapy. However, prospective evaluation, perhaps in randomized trials, is needed.

Background: Age-related epigenetic dysregulations are associated with several diseases, including cancer. The number of stochastic epigenetic mutations (SEM) has been suggested as a biomarker of life-course accumulation of exposure-related DNA damage; however, the predictive role of SEMs in cancer has seldom been investigated. Methods: A SEM, at a given CpG site, was defined as an extreme outlier of DNA methylation value distribution across individuals. We investigated the association of the total number of SEMs with the risk of eight cancers in 4,497 case–control pairs nested in three prospective cohorts. Furthermore, we investigated whether SEMs were randomly distributed across the genome or enriched in functional genomic regions. Results: In the three-study meta-analysis, the estimated ORs per one-unit increase in log(SEM) from logistic regression models adjusted for age and cancer risk factors were 1.25; 95% confidence interval (CI), 1.11–1.41 for breast cancer, and 1.23; 95% CI, 1.07–1.42 for lung cancer. In the Melbourne Collaborative Cohort Study, the OR for mature B-cell neoplasm was 1.46; 95% CI, 1.25–1.71. Enrichment analyses indicated that SEMs frequently occur in silenced genomic regions and in transcription factor binding sites regulated by EZH2 and SUZ12 (P < 0.0001 and P = 0.0005, respectively): two components of the polycomb repressive complex 2 (PCR2). Finally, we showed that PCR2-specific SEMs are generally more stable over time compared with SEMs occurring in the whole genome. Conclusions: The number of SEMs is associated with a higher risk of different cancers in prediagnostic blood samples. Impact: We identified a candidate biomarker for cancer early detection, and we described a carcinogenesis mechanism involving PCR2 complex proteins worthy of further investigations.

Abstract Background Conventional miltefosine dosing (2.5 mg/kg/day) for treatment of visceral leishmaniasis (VL) is less effective in children than in adults. A higher allometric dose (median 3.2 mg/kg/day) was therefore investigated in paediatric VL patients in Eastern Africa. Results of this trial showed an unforeseen, lower than dose-proportional increase in exposure. Therefore, we performed a pooled model-based analysis of the paediatric data available from both dosing regimens to characterize observed non-linearities in miltefosine pharmacokinetics (PK). Methods Fifty-one children with VL were included in this analysis, treated with either a conventional (n = 21) or allometric (n = 30) miltefosine dosing regimen. PK data were analysed using non-linear mixed-effects modelling. Results A two-compartment model following first-order absorption and linear elimination, with two separate effects on relative oral bioavailability, was found to fit these data best. A 69% lower bioavailability at treatment start was estimated, presumably due to initial malnourishment and malabsorption. Stagnation in miltefosine accumulation in plasma, hampering increased drug exposure, was related to the increase in cumulative dose (mg/kg/day). However, the allometric regimen increased exposure 1.7-fold in the first treatment week and reduced the time to reach the PK target by 17.4%. Conclusions Miltefosine PK in children suffering from VL are characterized by dose-dependent non-linearities that obstruct the initially expected exposure levels. Bioavailability appeared to be affected by the cumulative dose, possibly as a consequence of impaired absorption. Despite this, allometric dosing led to a faster target achievement and increased exposure compared with conventional dosing.

Parkinson`s disease (PD) is a progressive neurodegenerative disorder involving dopaminergic neurons from the substantia nigra. The loss of dopaminergic neurons results in decreased dopamine (DA) release in the striatum and thus impaired motor functions. DA is one of the key neurotransmitters monitored for the diagnosis, and during the progression and treatment of PD. Therefore, sensitive and selective DA detection methods are of high clinical relevance. In this study, a new microfluidic device utilized for electrochemical DA detection is reported. The microfluidic sensing device operates in the range of 0.1 - 1000 nM DA requiring only ~ 2.4 µL sample volume, which corresponds to detectable 240 amol of DA. Using this sensor, we were able to monitor the changes in DA levels in cerebrospinal fluid (CSF) and plasma of a mouse model of PD and following the treatment of drug L-3,4-dihydroxyphenylalanine (L-DOPA), which reversed the parkinsonian symptoms in PD mice.