The effect of tumor composition on the success of adaptive therapy: The case of metastatic Castrate-Resistant Prostate Cancer.

Prostate-specific antigen (PSA) is the most commonly used serum marker for prostate cancer. It plays a role in cancer detection, treatment monitoring, and more recently, in guiding adaptive therapy protocols, where treatment is alternated based on PSA levels. However, the relationship between PSA levels and tumor volume remains poorly understood. Empirical evidence suggests that different cancer cell types produce varying amounts of PSA. Despite this, current mathematical cancer models often assume either that all cell types contribute equally to PSA levels or that only certain subpopulations produce PSA at fixed rates. In this study, we compare Zhang et al.'s classical adaptive therapy protocol with the standard of care, which involves continuous maximum tolerable dose treatment, under different assumptions regarding PSA production. Specifically, we explore the possibility that testosterone-dependent, testosterone-producing, and testosterone-independent cells contribute to PSA production to varying degrees. We use the time to competitive release as a proxy for the time to disease progression. Our findings indicate that adaptive therapy consistently results in a longer time to competitive release compared to the standard of care, regardless of the assumptions about PSA production. However, when testosterone-independent cells are the sole PSA producers, Zhang et al.'s adaptive therapy protocol becomes inapplicable, as PSA levels never fall to half of their initial value, preventing therapy discontinuation. Additionally, we observe that the number and duration of treatment cycles in adaptive therapy are highly sensitive to assumptions about how much each cell type contributes to PSA production. Overall, our results emphasize the need for a deeper understanding of patient-specific PSA dynamics, which could enhance the effectiveness of adaptive therapy in prostate cancer treatment.

Plasticity for the win: Flexible transcriptional response to host plant switches in the comma butterfly (Polygonia c-album).

Generalist plant-feeding insects are characterised by a broad host repertoire that can comprise several families or even different orders of plants. The genetic and physiological mechanisms underlying the use of such a wide host range are still not fully understood. Earlier studies indicate that the consumption of different host plants is associated with host-specific gene expression profiles. It remained, however, unclear if and how larvae can alter these profiles in the case of a changing host environment. Using the polyphagous comma butterfly (Polygonia c-album) we show that larvae can adjust their transcriptional profiles in response to a new host plant. The switch to some of the host plants, however, resulted in a larger transcriptional response and, thus, seems to be more challenging. At a physiological level, no correspondence for these patterns could be found in larval performance. This suggests that a high transcriptional but also phenotypic flexibility are essential for the use of a broad and diverse host range. We furthermore propose that host switch tests in the laboratory followed by transcriptomic investigations can be a valuable tool to examine not only plasticity in host use but also subtle and/or transient trade-offs in the evolution of host plant repertoires.

The MYCN oncoprotein is an RNA-binding accessory factor of the nuclear exosome targeting complex.

The MYCN oncoprotein binds active promoters in a heterodimer with its partner protein MAX. MYCN also interacts with the nuclear exosome, a 3'-5' exoribonuclease complex, suggesting a function in RNA metabolism. Here, we show that MYCN forms stable high-molecular-weight complexes with the exosome and multiple RNA-binding proteins. MYCN binds RNA in vitro and in cells via a conserved sequence termed MYCBoxI. In cells, MYCN associates with thousands of intronic transcripts together with the ZCCHC8 subunit of the nuclear exosome targeting complex and enhances their processing. Perturbing exosome function results in global re-localization of MYCN from promoters to intronic RNAs. On chromatin, MYCN is then replaced by the MNT(MXD6) repressor protein, inhibiting MYCN-dependent transcription. RNA-binding-deficient alleles show that RNA-binding limits MYCN's ability to activate cell growth-related genes but is required for MYCN's ability to promote progression through S phase and enhance the stress resilience of neuroblastoma cells.

Targeting MYC effector functions in pancreatic cancer by inhibiting the ATPase RUVBL1/2.

OBJECTIVE: The hallmark oncogene MYC drives the progression of most tumours, but direct inhibition of MYC by a small-molecule drug has not reached clinical testing. MYC is a transcription factor that depends on several binding partners to function. We therefore explored the possibility of targeting MYC via its interactome in pancreatic ductal adenocarcinoma (PDAC). DESIGN: To identify the most suitable targets among all MYC binding partners, we constructed a targeted shRNA library and performed screens in cultured PDAC cells and tumours in mice. RESULTS: Unexpectedly, many MYC binding partners were found to be important for cultured PDAC cells but dispensable in vivo. However, some were also essential for tumours in their natural environment and, among these, the ATPases RUVBL1 and RUVBL2 ranked first. Degradation of RUVBL1 by the auxin-degron system led to the arrest of cultured PDAC cells but not untransformed cells and to complete tumour regression in mice, which was preceded by immune cell infiltration. Mechanistically, RUVBL1 was required for MYC to establish oncogenic and immunoevasive gene expression identifying the RUVBL1/2 complex as a druggable vulnerability in MYC-driven cancer. CONCLUSION: One implication of our study is that PDAC cell dependencies are strongly influenced by the environment, so genetic screens should be performed in vitro and in vivo. Moreover, the auxin-degron system can be applied in a PDAC model, allowing target validation in living mice. Finally, by revealing the nuclear functions of the RUVBL1/2 complex, our study presents a pharmaceutical strategy to render pancreatic cancers potentially susceptible to immunotherapy.

[Establishment of the new "Health Data Lab" to provide data for science]. / Aufbau des neuen "Forschungsdatenzentrums Gesundheit" zur Datenbereitstellung für die Wissenschaft.

The analysis of real-world data (RWD) has become increasingly important in health research in recent years. With the BfArM Health Data Lab (HDL), which is currently being set up, researchers will in future be able to gain access to routine data from the statutory health insurance of around 74 million people in Germany. Data from electronic patient records can also be made available for research prospectively. In doing so, the Health Data Lab guarantees the highest data protection and IT security standards. The digital application process, the provision of data in secure processing environments as well as the features supporting the analyses such as catalogues of coding systems, a point-and-click analysis tool and predefined standard analyses increase user-friendliness for researchers. The use of the extensive health data accessible at HDL will open a wide range of future possibilities for improving the health system and the quality of care. This article begins by highlighting the advantages of the HDL and outlining the opportunities that the RWD offers for research in healthcare and for the population. The structure and central aspects of the HDL are explained afterwards. An outlook on the opportunities of linking different data is given. What the application and data usage processes at the HDL will look like is illustrated using the example of fictitious possibilities for analysing long COVID based on the routine data available at the HDL in the future.

Relative importance of speech and voice features in the classification of schizophrenia and depression.

Speech is a promising biomarker for schizophrenia spectrum disorder (SSD) and major depressive disorder (MDD). This proof of principle study investigates previously studied speech acoustics in combination with a novel application of voice pathology features as objective and reproducible classifiers for depression, schizophrenia, and healthy controls (HC). Speech and voice features for classification were calculated from recordings of picture descriptions from 240 speech samples (20 participants with SSD, 20 with MDD, and 20 HC each with 4 samples). Binary classification support vector machine (SVM) models classified the disorder groups and HC. For each feature, the permutation feature importance was calculated, and the top 25% most important features were used to compare differences between the disorder groups and HC including correlations between the important features and symptom severity scores. Multiple kernels for SVM were tested and the pairwise models with the best performing kernel (3-degree polynomial) were highly accurate for each classification: 0.947 for HC vs. SSD, 0.920 for HC vs. MDD, and 0.932 for SSD vs. MDD. The relatively most important features were measures of articulation coordination, number of pauses per minute, and speech variability. There were moderate correlations between important features and positive symptoms for SSD. The important features suggest that speech characteristics relating to psychomotor slowing, alogia, and flat affect differ between HC, SSD, and MDD.

Syntactic complexity and diversity of spontaneous speech production in schizophrenia spectrum and major depressive disorders.

Syntax, the grammatical structure of sentences, is a fundamental aspect of language. It remains debated whether reduced syntactic complexity is unique to schizophrenia spectrum disorder (SSD) or whether it is also present in major depressive disorder (MDD). Furthermore, the association of syntax (including syntactic complexity and diversity) with language-related neuropsychology and psychopathological symptoms across disorders remains unclear. Thirty-four SSD patients and thirty-eight MDD patients diagnosed according to DSM-IV-TR as well as forty healthy controls (HC) were included and tasked with describing four pictures from the Thematic Apperception Test. We analyzed the produced speech regarding its syntax delineating measures for syntactic complexity (the total number of main clauses embedding subordinate clauses) and diversity (number of different types of complex sentences). We performed cluster analysis to identify clusters based on syntax and investigated associations of syntactic, to language-related neuropsychological (verbal fluency and verbal episodic memory), and psychopathological measures (positive and negative formal thought disorder) using network analyses. Syntax in SSD was significantly reduced in comparison to MDD and HC, whereas the comparison of HC and MDD revealed no significant differences. No associations were present between speech measures and current medication, duration and severity of illness, age or sex; the single association accounted for was education. A cluster analysis resulted in four clusters with different degrees of syntax across diagnoses. Subjects with less syntax exhibited pronounced positive and negative symptoms and displayed poorer performance in executive functioning, global functioning, and verbal episodic memory. All cluster-based networks indicated varying degrees of domain-specific and cross-domain connections. Measures of syntactic complexity were closely related while syntactic diversity appeared to be a separate node outside of the syntactic network. Cross-domain associations were more salient in more complex syntactic production.

Modulation of proper name recall by transcranial direct current stimulation of the anterior temporal lobes.

We often fail to recall another person's name. Proper names might be more difficult to memorize and retrieve than other pieces of knowledge, such as one's profession because they are processed differently in the brain. Neuroimaging and neuropsychological studies associate the bilateral anterior temporal lobes (ATL) in the retrieval of proper names and other person-related knowledge. Specifically, recalling a person's name is thought to be supported by the left ATL, whereas recalling specific information such as a person's occupation is suggested to be subserved by the right ATL. To clarify and further explore the causal relationship between both ATLs and proper name retrieval, we stimulated these regions with anodal, cathodal and sham transcranial direct current stimulation (tDCS) while the participants memorized surnames (e.g., Mr. Baker) and professions (e.g., baker) presented with a person's face. The participants were then later asked to recall the surname and the profession. Left ATL anodal stimulation resulted in higher intrusion errors for surnames than sham, whereas right ATL anodal stimulation resulted in higher overall intrusion errors, both, surnames and professions, compared to cathodal stimulation. Cathodal stimulation of the left and right ATL had no significant effect on surname and profession recall. The results indicate that the left ATL plays a role in recalling proper names. On the other hand, the specific role of the right ATL remaines to be explored.

Green Tea Extract to Prevent Colorectal Adenomas, Results of a Randomized, Placebo-Controlled Clinical Trial.

INTRODUCTION: Preclinical, epidemiological, and small clinical studies suggest that green tea extract (GTE) and its major active component epigallocatechingallate (EGCG) exhibit antineoplastic effects in the colorectum. METHODS: A randomized, double-blind trial of GTE standardized to 150 mg of EGCG b.i.d. vs placebo over 3 years was conducted to prevent colorectal adenomas (n = 1,001 with colon adenomas enrolled, 40 German centers). Randomization (1:1, n = 879) was performed after a 4-week run-in with GTE for safety assessment. The primary end point was the presence of adenoma/colorectal cancer at the follow-up colonoscopy 3 years after randomization. RESULTS: The safety profile of GTE was favorable with no major differences in adverse events between the 2 well-balanced groups. Adenoma rate in the modified intention-to-treat set (all randomized participants [intention-to-treat population] and a follow-up colonoscopy 26-44 months after randomization; n = 632) was 55.7% in the placebo and 51.1% in the GTE groups. This 4.6% difference was not statistically significant (adjusted relative risk 0.905; P = 0.1613). The respective figures for the per-protocol population were 54.3% (151/278) in the placebo group and 48.3% (129/267) in the GTE group, indicating a slightly lower adenoma rate in the GTE group, which was not significant (adjusted relative risk 0.883; P = 0.1169). DISCUSSION: GTE was well tolerated, but there was no statistically significant difference in the adenoma rate between the GTE and the placebo groups in the whole study population.

Patient Centered Radiology - An Introduction in Form of a Narrative Review. / Patientenzentrierte Radiologie ­ Eine Hinführung durch ein narratives Review.

BACKGROUND: Patient centered radiology represents a crucial aspect for modern sustainable radiology. The definition of patient-centered consists of a focus on patients' individual values and wishes with a respectful integration in medical decisions. In this narrative review we try to give a practical introduction into this complex topic with the extension to a person-centered radiology, which additionally encompasses values and wishes of radiological and other medical colleagues. METHODS: Medline search between 2010 and 2021 using "patient-centered radiology" with additional subjective selection of articles for this narrative review. RESULTS: Regarding patients' experiences the main literature focus were patients' fears of examinations (movement restrictions, uncertainty). Most patients would prefer a direct communication with the radiologist after the examination. Regarding interdisciplinary communication the radiological expertise and quality is highly appreciated; however, there was a general wish for more structured- or itemized reporting. Concerning working conditions radiologists were satisfied despite high psychosocial working pressure. CONCLUSION: Most of the literature on this topic consists of surveys evaluating the current state. Studies on interventions such as improved information before examinations or patient-readable reports are still scarce. There is a dilemma between an increasing radiological workload and the simultaneous wish for more patient-centered approaches such as direct radiologist-patient communications in the daily routine. Still on our way to a more value-based radiology we have to focus on patient communications and a patient-centered medicine. KEY POINTS: · Patient centered radiology has a focus on the integration of patients' individual values and wishes in their decisions.. · Radiologists are clinicians, who an additional diagnostic and therapeutic surplus for patients and referring physicians.. · The recent literature on this topic consists basically on the evaluation of the current status.. · Most patients prefer a direct communication with the radiologist.. · To gain a "value based" radiology we to focus on an optimized communication with patients and referring physicians.. CITATION FORMAT: · Schreyer AG, Schneider K, Dendl LM et al. Patient Centered Radiology - An Introduction in Form of a Narrative Review. Fortschr Röntgenstr 2022; 194: 873 - 881.

Exposure of wild boar to Influenza A viruses in Bavaria: Analysis of seroprevalences and antibody subtype specificity before and after the panzootic of highly pathogenic avian influenza viruses A (H5N8).

Swine influenza A viruses (S-IAV) circulate in wild boar populations worldwide. Subtypes primarily reflect those actually present within the respective pig industry. Accordingly, infections with swine H1N1, H1N2 and H3N2 have been reported for several regions of Germany. As pigs are susceptible not only to S-IAV but also to avian and human influenza A viruses, it is necessary to consider the possibility that new reassortant viruses with pandemic potential may arise in these new hosts. Therefore, in this study the impact of recent IAV epidemics on antibody prevalences in Bavarian wild boar was assessed. Important events considered were the H1N1pdm09 pandemic, which affected humans and swine, and the highly pathogenic avian influenza (HPAI) H5N8 panzootic in 2016 and 2017, affecting wild and domestic birds. IAV seroprevalences were determined analysing 1,396 samples from before and after the H5N8 panzootic, from various regions in Bavaria, a large administrative region in the South of Germany. Taken together, seroprevalences varied markedly from 1.44% to 12.59%, relative to region and time. However, no discrete correlation was found to population density either in wild boar or in pigs. Antibodies against H1N1 were the most prevalent. In addition, antibodies were detected reacting against H1N2 and against H1pdmNx reassortant viruses, already known to circulate in domestic pigs in Bavaria and notably also against the avian influenza A virus H5N8; the latter in samples taken in 2017. These results confirm the exposure of wild boar to IAV of diverse origin and the increasing variability of S-IAV present in the field. The necessity for continuous IAV surveillance not only of domestic swine but also of wildlife is emphasized.

Effects of genetic variability of CYP2D6 on neural substrates of sustained attention during on-task activity.

The polymorphic drug-metabolizing enzyme CYP2D6, which is responsible for the metabolism of most psychoactive compounds, is expressed not only in the liver, but also in the brain. The effects of its marked genetic polymorphism on the individual capacity to metabolize drugs are well known, but its role in metabolism of neural substrates affecting behavior personality or cognition, suggested by its CNS expression, is a long-standing unresolved issue. To verify earlier findings suggesting a potential effect on attentional processes, we collected functional imaging data, while N = 415 participants performed a simple task in which the reward for correct responses varied. CYP2D6 allelic variants predicting higher levels of enzymatic activity level were positively associated with cortical activity in occipito-parietal areas as well as in a right lateralized network known to be activated by spatial attentional tasks. Reward-related modulation of activity in cortical areas was more pronounced in poor metabolizers. In conjunction with effects on reaction times, our findings provide evidence for reduced cognitive efficiency in rapid metabolizers compared to poor metabolizers in on-task attentional processes manifested through differential recruitment of a specific neural substrate.

Subtherapeutic bupropion and hydroxybupropion serum concentrations in a patient with CYP2C19*1/*17 genotype suggesting a rapid metabolizer status.

Bupropion is hydroxylated to its primary active metabolite hydroxybupropion by cytochrome P450 enzyme CYP2B6. In vitro data suggest the existence of alternative hydroxylation pathways mediated by the highly polymorphic enzyme CYP2C19. However, the impact of its genetic variants on bupropion metabolism in vivo is still under investigation. We report the case of a 28-year-old male Caucasian outpatient suffering from major depressive disorder who did not respond to a treatment with bupropion. Therapeutic drug monitoring revealed very low serum concentrations of both bupropion and hydroxybupropion. Genotyping identified a heterozygous status for the gain-of-function allele with the genotype CYP2C19*1/*17 predicting enhanced enzymatic activity. The present case shows a reduced bupropion efficacy, which may be explained by a reduced active moiety of bupropion and its active metabolite hydroxybupropion, due to alternative hydroxylation pathways mediated by CYP2C19 in an individual with CYP2C19 rapid metabolizer status. The case report thus illustrates the clinical relevance of therapeutic drug monitoring in combination with pharmacogenetics diagnostics for a personalized treatment approach.

Parkin contributes to synaptic vesicle autophagy in Bassoon-deficient mice.

Mechanisms regulating the turnover of synaptic vesicle (SV) proteins are not well understood. They are thought to require poly-ubiquitination and degradation through proteasome, endo-lysosomal or autophagy-related pathways. Bassoon was shown to negatively regulate presynaptic autophagy in part by scaffolding Atg5. Here, we show that increased autophagy in Bassoon knockout neurons depends on poly-ubiquitination and that the loss of Bassoon leads to elevated levels of ubiquitinated synaptic proteins per se. Our data show that Bassoon knockout neurons have a smaller SV pool size and a higher turnover rate as indicated by a younger pool of SV2. The E3 ligase Parkin is required for increased autophagy in Bassoon-deficient neurons as the knockdown of Parkin normalized autophagy and SV protein levels and rescued impaired SV recycling. These data indicate that Bassoon is a key regulator of SV proteostasis and that Parkin is a key E3 ligase in the autophagy-mediated clearance of SV proteins.

Diagnosis and Empirical Treatment of Urinary Tract Infections in Urologic Outpatients.

INTRODUCTION: Due to a continuing increase of bacterial resistance in common uropathogens, we wanted to revisit our standards for the diagnosis and treatment of lower urinary tract infections, in the setting of urological outpatient care in a conurbation in Germany. PATIENTS AND METHODS: All subjects presenting with significant bacteriuria at our urology clinics in Mülheim, Germany, in 2011 were included. Comorbidity, bacterial species, urinary tract symptoms, and empirically prescribed antibiotics were taken from the patients' records. RESULTS: In 2011, a total of 1,324 patients were included (793 female, 531 male). Of the 771 patients with symptomatic bacteriuria, 647 received antibiotic treatment, as well as 116 of 409 patients with asymptomatic bacteriuria. Escherichia coli was identified in 60% of the included patients. In 427 E. coli infections, bacterial resistance was found in 14% of 316 cases treated with quinolone, in 21% of 53 cases treated with co-trimoxazole, and in only 3% of 58 cases treated with nitrofurantoin. CONCLUSIONS: We found a high use of fluoroquinolones for empirical first-line antibiotics in the treatment of lower urinary tract infections. In our regional setting, antibiotic stewardship needs to be promoted, along national and international guidelines, to avoid unnecessary prescription of fluoroquinolones for empirical treatment.

Bovine Alphaherpesvirus 2 infections in Bavaria: an analysis of the current situation - several years after eradicating Bovine Alphaherpesvirus 1.

BACKGROUND: Bavaria, a large federal state in Germany, has been declared free from infections with Bovine Alphaherpesvirus 1 (BoHV-1) in 2011. To maintain this status the cattle population is monitored for antibodies against BoHV-1 regularly. Several years ago, infrequent but recurrent problems in this sero-surveillance were statistically put into correlation with the presence of antibodies against Bovine Alphaherpesvirus 2 (BoHV-2). In Europe, BoHV-2 is primarily known as the agent causing bovine herpes mammillitis. However, very little information about BoHV-2 infections in Bavaria is available so far. Therefore, the aims of this study were to determine BoHV-2 seroprevalences and to detect virus genomes in potential clinical samples. RESULTS: 6801 blood sera of healthy cattle from all over Bavaria were tested for antibodies against BoHV-2, revealing an overall seroprevalence of 5.51%. Interestingly, seroprevalences markedly varied between the North and the South of Bavaria, namely from 0.42 to 11.17%. Concurrently, the previously reported relation between the epidemiologically inexplicable sero-reactivities in BoHV-1 ELISAs and the presence of BoHV-2 infections were statistically corroborated in this study. To detect BoHV-2 genomes a fast and sensitive real time PCR was established. Using a multiple PCR strategy, tissue samples from skin lesions at relevant localizations, corresponding lymph nodes, and trigeminal ganglia from 111 animals, as well as nasal swabs from 918 bovines with respiratory symptoms were tested. However, BoHV-2 genomes were not detected in any of these samples. CONCLUSIONS: BoHV-2 antibodies were found in samples from bovines all over Bavaria, albeit with an explicit South-North-divide. BoHV-2 genomes, however, could not be detected in any of the analyzed samples, indicating that acute clinical cases as well as obvious virus reactivation are relatively rare. Consequently, the future spread of BoHV-2 infections throughout Bavaria, particularly, after eradicating BoHV-1, has to be further monitored.

Vascular response to social cognitive performance measured by infrared thermography: A translational study from mouse to man.

To assess complex social recognition in mice, we previously developed the SocioBox paradigm. Unexpectedly, 4 weeks after performing in the SocioBox, mice displayed robust social avoidance during Y-maze sociability testing. This unique "sociophobia" acquisition could be documented in independent cohorts. We therefore employed infrared thermography as a non-invasive method of stress-monitoring during SocioBox testing (presentation of five other mice) versus empty box. A higher Centralization Index (body/tail temperature) in the SocioBox correlated negatively with social recognition memory and, after 4 weeks, with social preference in the Y-maze. Assuming that social stimuli might be associated with characteristic thermo-responses, we exposed healthy men (N = 103) with a comparably high intelligence level to a standardized test session including two cognitive tests with or without social component (face versus pattern recognition). In some analogy to the Centralization Index (within-subject measure) used in mice, the Reference Index (ratio nose/malar cheek temperature) was introduced to determine the autonomic facial response/flushing during social recognition testing. Whereas cognitive performance and salivary cortisol were comparable across human subjects and tests, the Face Recognition Test was associated with a characteristic Reference Index profile. Infrared thermography may have potential for discriminating disturbed social behaviors.