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Highly abundant in mammals, collagens define the organization of tissues and participate in cell signalling. Most of the 28 vertebrate collagens, with the exception of collagens VI, VII, XXVI and XXVIII, can be categorized into five subgroups: fibrillar collagens, network-forming collagens, fibril-associated collagens with interrupted triple helices, membrane-associated collagens with interrupted triple helices and multiple triple-helix domains with interruptions. Collagen peptides are synthesized from the ribosome and enter the rough endoplasmic reticulum, where they undergo numerous post-translational modifications. The collagen chains form triple helices that can be secreted to form a diverse array of supramolecular structures in the extracellular matrix. Collagens are ubiquitously expressed and have been linked to a broad spectrum of disorders, including genetic disorders with kidney phenotypes. They also have an important role in kidney fibrosis and mass spectrometry-based proteomic studies have improved understanding of the composition of fibrosis in kidney disease. A wide range of therapeutics are in development for collagen and kidney disorders, including genetic approaches, chaperone therapies, protein degradation strategies and anti-fibrotic therapies. Improved understanding of collagens and their role in disease is needed to facilitate the development of more specific treatments for collagen and kidney disorders. Collagens are ubiquitously expressed and have been linked to a broad spectrum of disorders. Here, the authors discuss collagen subtypes and provide a summary of collagen disorders, fibrotic process and therapies, with an emphasis on kidney diseases. Key points: Collagens are highly abundant in vertebrates and have critical roles in structural integrity, tissue organization and signalling. Collagens undergo a series of processing events that begin with trafficking into the rough endoplasmic reticulum and post-translational modification. Pathogenic variants in collagen genes are associated with a spectrum of disorders. In the kidney, collagen variants cause Alport syndrome, congenital abnormalities of the kidney and urinary tract and the multisystem disorder, Gould syndrome. Dysregulated collagens are also a hallmark of fibrosis, which is a major cause of organ failure. Current and future therapies for collagen disorders and kidney diseases can be broadly categorized as genetic approaches, chaperone therapies, protein degradation strategies and anti-fibrotic therapies. [ABSTRACT FROM AUTHOR]

Purpose: The radionuclide pair cerium-134/lanthanum-134 (134Ce/134La) was recently proposed as a suitable diagnostic counterpart for the therapeutic alpha-emitter actinium-225 (225Ac). The unique properties of 134Ce offer perspectives for developing innovative in vivo investigations that are not possible with 225Ac. In this work, 225Ac- and 134Ce-labelled tracers were directly compared using internalizing and slow-internalizing cancer models to evaluate their in vivo comparability, progeny meandering, and potential as a matched theranostic pair for clinical translation. Despite being an excellent chemical match, 134Ce/134La has limitations to the setting of quantitative positron emission tomography imaging. Methods: The precursor PSMA-617 and a macropa-based tetrazine-conjugate (mcp-PEG8-Tz) were radiolabelled with 225Ac or 134Ce and compared in vitro and in vivo using standard (radio)chemical methods. Employing biodistribution studies and positron emission tomography (PET) imaging in athymic nude mice, the radiolabelled PSMA-617 tracers were evaluated in a PC3/PIP (PC3 engineered to express a high level of prostate-specific membrane antigen) prostate cancer mouse model. The 225Ac and 134Ce-labelled mcp-PEG8-Tz were investigated in a BxPC-3 pancreatic tumour model harnessing the pretargeting strategy based on a trans-cyclooctene-modified 5B1 monoclonal antibody. Results: In vitro and in vivo studies with both 225Ac and 134Ce-labelled tracers led to comparable results, confirming the matching pharmacokinetics of this theranostic pair. However, PET imaging of the 134Ce-labelled precursors indicated that quantification is highly dependent on tracer internalization due to the redistribution of 134Ce's PET-compatible daughter 134La. Consequently, radiotracers based on internalizing vectors like PSMA-617 are suited for this theranostic pair, while slow-internalizing 225Ac-labelled tracers are not quantitatively represented by 134Ce PET imaging. Conclusion: When employing slow-internalizing vectors, 134Ce might not be an ideal match for 225Ac due to the underestimation of tumour uptake caused by the in vivo redistribution of 134La. However, this same characteristic makes it possible to estimate the redistribution of 225Ac's progeny noninvasively. In future studies, this unique PET in vivo generator will further be harnessed to study tracer internalization, trafficking of receptors, and the progression of the tumour microenvironment. [ABSTRACT FROM AUTHOR]

Research into the mobility of researchers has garnered increasing interest among institutions and governments. In this study, we use ORCID as a data source to analyse the mobility of researchers trained in Germany, France, Spain, the Netherlands, and Italy, the main economies of the Eurozone according to Gross Domestic Product (GDP). Our approach focuses on the connection between the place of education and employment, identifying graduates and their countries of employment through profiles on ORCID. We conduct a comparative analysis of preferred destinations, considering various levels of education, and develop a migration rate for researchers from these countries. The results reveal a clear preference for the United States and Great Britain among graduates, influenced by linguistic affinities and historical cultural relations. Regarding the migration rate, we observe that all countries retain more graduates than those who emigrate. France leads in emigration, followed by the Netherlands, Germany, Italy, and Spain. This analysis of researcher mobility in the Eurozone allows us to track migratory flows, identifying both sending and receiving countries. These findings are essential for the formulation of scientific and migration policies and contribute to understanding individual behaviour in building academic and professional careers. [ABSTRACT FROM AUTHOR]

Lévy processes time-changed by inverse subordinators have been intensively studied in the last years. Their importance in connection with non-local operators and semi-Markov dynamics is well understood, but, in our view, several questions remain open concerning the probabilistic structure of such processes. The time-changed Lévy processes are particularly useful to describe complex systems with fractional and/or anomalous dynamics. The purpose of our work is to analyze the features of the sample paths of such processes, focusing on a martingale-based approach. We introduce the fractional Poisson random measure as the main tool for dealing with the jump component of time-changed càdlàg processes. Further, the fractional random measure is an interesting and novel topic in itself, and thus, it is thoroughly analyzed in the paper. A central role in our analysis is then played by fractional Poisson integrals (involving the aforementioned fractional Poisson measure) which allow a useful description of the random jumps. We investigate these stochastic integrals and the martingale property of their compensated counterpart. Therefore, we are able to obtain a semimartingale representation of time-changed processes analogous to the celebrated Lévy–Itô decomposition. Finally, an approximation scheme of such random processes will be discussed. [ABSTRACT FROM AUTHOR]

Random flights (also called run-and-tumble walks or transport processes) represent finite velocity random motions changing direction at any Poissonian time. These models in d-dimension, can be studied giving a general formulation of the problem valid at any spatial dimension. The aim of this paper is to extend this general analysis to time-fractional processes arising from a non-local generalization of the kinetic equations. The probabilistic interpretation of the solution of the time-fractional equations leads to a time-changed version of the original transport processes. The obtained results provide a clear picture of the role played by the time-fractional derivatives in this kind of random motions. They display an anomalous behavior and are useful to describe several complex systems arising in statistical physics and biology. In particular, we focus on the one-dimensional random flight, called telegraph process, studying the time-fractional version of the classical telegraph equation and providing a suitable interpretation of its stochastic solutions. [ABSTRACT FROM AUTHOR]

Languages are grouped into families that share common linguistic traits. While this approach has been successful in understanding genetic relations between diverse languages, more analyses are needed to accurately quantify their relatedness, especially in less studied linguistic levels such as syntax. Here, we explore linguistic distances using series of parts of speech (POS) extracted from the Universal Dependencies dataset. Within an information-theoretic framework, we show that employing POS trigrams maximizes the possibility of capturing syntactic variations while being at the same time compatible with the amount of available data. Linguistic connections are then established by assessing pairwise distances based on the POS distributions. Intriguingly, our analysis reveals definite clusters that correspond to well known language families and groups, with exceptions explained by distinct morphological typologies. Furthermore, we obtain a significant correlation between language similarity and geographic distance, which underscores the influence of spatial proximity on language kinships. [ABSTRACT FROM AUTHOR]

Background: Senescence is a cellular aging-related process triggered by different stresses and characterized by the secretion of various inflammatory factors referred to as senescence-associated secretory phenotype (SASP), some of which are produced by the NLRP3 inflammasome. Here, we present evidence that the NLRP1 inflammasome is a DNA damage sensor and a key mediator of senescence. Methods: Senescence was induced in fibroblasts in vitro and in mice. Cellular senescence was assessed by Western blot analysis of several proteins, including p16, p21, p53, and SASP factors, released in the culture media or serum. Inflammasome components, including NLRP1, NLRP3 and GSDMD were knocked out or silenced using siRNAs. Results: In vitro and in vivo results suggest that the NLRP1 inflammasome promotes senescence by regulating the expression of p16, p21, p53, and SASP factors in a Gasdermin D (GSDMD)-dependent manner. Mechanistically, the NLRP1 inflammasome is activated in response to genomic damage detected by the cytosolic DNA sensor cGMP-AMP (cGAMP) synthase (cGAS). Conclusion: Our findings show that NLRP1 is a cGAS-dependent DNA damage sensor during senescence and a mediator of SASP release through GSDMD. This study advances the knowledge on the biology of the NLRP1 inflammasome and highlights this pathway as a potential pharmcological target to modulate senescence. [ABSTRACT FROM AUTHOR]

Methadone is a synthetic long-acting opioid that is increasingly used in the replacement therapy of opioid-addicted patients, including pregnant women. However, methadone therapy in this population poses challenges, as it induces cognitive and behavioral impairments in infants exposed to this opioid during prenatal development. In animal models, prenatal methadone exposure results in detrimental consequences to the central nervous system, such as: (i) increased neuronal apoptosis; (ii) disruption of oligodendrocyte maturation and increased apoptosis and (iii) increased microglia and astrocyte activation. However, it remains unclear whether these deleterious effects result from a direct effect of methadone on brain cells. Therefore, our goal was to uncover the impact of methadone on single brain cell types in vitro. Primary cultures of rat neurons, oligodendrocytes, microglia, and astrocytes were treated for three days with 10 µM methadone to emulate a chronic administration. Apoptotic neurons were identified by cleaved caspase-3 detection, and synaptic density was assessed by the juxtaposition of presynaptic and postsynaptic markers. Apoptosis of oligodendrocyte precursors was determined by cleaved caspase-3 detection. Oligodendrocyte myelination was assessed by immunofluorescence, while microglia and astrocyte proinflammatory activation were assessed by both immunofluorescence and RT-qPCR. Methadone treatment increased neuronal apoptosis and reduced synaptic density. Furthermore, it led to increased oligodendrocyte apoptosis and a reduction in the myelinating capacity of these cells, and promoted the proinflammatory activation of microglia and astrocytes. We showed that methadone, the most widely used drug in opioid replacement therapy for pregnant women with opioid addiction, directly impairs brain cells in vitro, highlighting the need for developing alternative therapies to address opioid addiction in this population. [ABSTRACT FROM AUTHOR]

While European regions face a range of different climate hazards, little is known about how these differences affect local climate adaptation planning. We present an analytical framework for evaluating local climate adaptation plans (LCAPs) and apply it to 327 cities in 28 countries across different European regions. To do this, we use statistical methods to identify regional clusters based on overall plan quality, impacts, vulnerable population groups, and sectors addressed by LCAPs. By comparing both geographic and statistical clusters, we found (1) significant spatial heterogeneity across European cities but (2) higher average plan quality scores and more consistent strategies across cities in Central and Eastern Europe. Notably, we found no regional differences regarding (a) the climate impacts and vulnerable communities identified in plans: (b) the most commonly addressed impacts, which were urban temperature and changing precipitation patterns; and (c) the residents that cities identified as most vulnerable, namely older people, women, infants, and the sick. Our study provides a spatial analysis of European LCAPs to uncover regional policy perspectives on local climate adaptation issues. Such approaches can effectively inform broader EU, national and regional strategies that aim to support local adaptation planning in a context of multi-level governance. [ABSTRACT FROM AUTHOR]

Natural polymers have found increased use in a wider range of applications due to their less harmful effects. Notably, bacterial cellulose has gained significant consideration due to its exceptional physical and chemical properties and its substantial biocompatibility, which makes it an attractive candidate for several biomedical applications. This study attempts to thoroughly unravel the microstructure of bacterial cellulose precursors, known as bioflocculants, which to date have been poorly characterised, by employing both electron and optical microscopy techniques. Here, starting from bioflocculants from Symbiotic Culture of Bacteria and Yeast (SCOBY), we proved that their microstructural features, such as porosity percentage, cellulose assembly degree, fibres' density and fraction, change in a spatio-temporal manner during their rising toward the liquid–air interface. Furthermore, our research identified a correlation between electron and optical microscopy parameters, enabling the assessment of bioflocculants' microstructure without necessitating offline sample preparation procedures. The ultimate goal was to determine their potential suitability as a novel cellulose-based building block material with tuneable structural properties. Our investigations substantiate the capability of SCOBY bioflocculants, characterized by distinct microstructures, to successfully assemble within a microfluidic device, thereby generating a cellulose sheet endowed with specific and purposefully designed structural features. [ABSTRACT FROM AUTHOR]

Purpose: The gastric adenocarcinoma (GC) represents the third cause of cancer-related mortality worldwide, and available therapeutic options remain sub-optimal. The Fibroblast growth factor receptors (FGFRs) are oncogenic transmembrane tyrosine kinase receptors. FGFR inhibitors have been approved for the treatment of various cancers and a STAT3-dependent regulation of FGFR4 has been documented in the H.pylori infected intestinal GC. Therefore, the modulation of FGFR4 might be useful for the treatment of GC. Methods: To investigate wich factors could modulate FGFR4 signalling in GC, we employed RNA-seq analysis on GC patients biopsies, human patients derived organoids (PDOs) and cancer cell lines. Results: We report that FGFR4 expression/function is regulated by the leukemia inhibitory factor (LIF) an IL-6 related oncogenic cytokine, in JAK1/STAT3 dependent manner. The transcriptomic analysis revealed a direct correlation between the expression of LIFR and FGFR4 in the tissue of an exploratory cohort of 31 GC and confirmed these findings by two external validation cohorts of GC. A LIFR inhibitor (LIR-201) abrogates STAT3 phosphorylation induced by LIF as well as recruitment of pSTAT3 to the promoter of FGFR4. Furthermore, inhibition of FGFR4 by roblitinib or siRNA abrogates STAT3 phosphorylation and oncogentic effects of LIF in GC cells, indicating that FGFR4 is a downstream target of LIF/LIFR complex. Treating cells with LIR-201 abrogates oncogenic potential of FGF19, the physiological ligand of FGFR4. Conclusions: Together these data unreveal a previously unregnized regulatory mechanism of FGFR4 by LIF/LIFR and demonstrate that LIF and FGF19 converge on the regulation of oncogenic STAT3 in GC cells. [ABSTRACT FROM AUTHOR]

Duets are one of the most fascinating displays in animal vocal communication, where two animals fine-tune the timing of their emissions to create a coordinated signal. Duetting behavior is widespread in the animal kingdom and is present in insects, birds, and mammals. Duets are essential to regulate activities within and between social units. Few studies assessed the functions of these vocal emissions experimentally, and for many species, there is still no consensus on what duets are used for. Here, we reviewed the literature on the function of duets in non-human primates, investigating a possible link between the social organization of the species and the function of its duetting behavior. In primates and birds, social conditions characterized by higher promiscuity might relate to the emergence of duetting behavior. We considered both quantitative and qualitative studies, which led us to hypothesize that the shift in the social organization from pair living to a mixed social organization might have led to the emergence of mate defense and mate guarding as critical functions of duetting behavior. Territory/resource ownership and defense functions are more critical in obligate pair-living species. Finally, we encourage future experimental research on this topic to allow the formulation of empirically testable predictions. [ABSTRACT FROM AUTHOR]

Patients with chronic myeloid leukemia (CML) treated with nilotinib or ponatinib may experience arterial occlusive events (AOEs). It is currently recommended to thoroughly assess cardiovascular risk factors before treating CML. We identified 455 consecutive CML adult patients, 335 treated with nilotinib and 120 with ponatinib; 380 patients without previous cardiovascular diseases or diabetes were stratified according to the Systematic Coronary Risk Evaluation (SCORE2) and SCORE2-Older Persons (SCORE2-OP). This updated algorithm from the European Society of Cardiology (ESC) estimates a 10-year risk of fatal and non-fatal cardiovascular diseases. It is based on sex, age, smoking habits, systolic blood pressure, non-high-density lipoprotein cholesterol, and European geographical region of cardiovascular risk. The SCORE2/SCORE2-OP algorithm translated more patients (50.2%) to the high–very high cardiovascular risk category than the previous SCORE (25.3%). Patients with a high to very high SCORE2/SCORE2-OP risk showed a significantly higher incidence rate of AOEs (69.2% vs. 46.5%, p < 0.001). The older SCORE was less specific in estimating AOEs in patients classified as low-intermediate risk (69.8 vs. 54.2%). In multivariate analysis, no associations were found between AOEs and gender, age, and type or dose of tyrosine kinase inhibitor. Only the SCORE2/SCORE2-OP risk was confirmed as a significant predictive factor (p = 0.028; hazard ratio = 2.2; 95% confidence interval = 1.1–4.5). Patients with AOEs required, in most cases, imaging diagnostic tests, additional drugs, and sometimes invasive procedures, increasing access to visits and hospital management. This real-life study suggested that the SCORE2 and SCORE2-OP charts could help identify cardiovascular fragility in CML patients providing them with more attention and a proper TKI selection. [ABSTRACT FROM AUTHOR]

Objectives: To evaluate the safety and efficacy of catheter-directed hemorrhoidal embolization (CDHE) by microcoil embolization for rectal bleeding due to hemorrhoids classified as Goligher grade I–III. Methods: Eighty patients (62.5% males) with a mean age of 48 ± 9 years were recruited prospectively. All patients had symptomatic bleeding hemorrhoids. All patients were classified according to Goligher classification: grade I (13.7%), grade II (71.1%), grade III (15%), and no grade IV were recruited in this study. In all cases, microcoils were used to embolize the superior rectal artery(SRA), and microspheres if recurrence of bleeding occurred. Follow-up evaluation (1, 3, 6, and 12 months) included clinical examination and anoscopy. A questionnaire was conducted to determine improvement regarding bleeding, quality of life before, and the degree of patient satisfaction of each participant. Results: Technical success was achieved in 100% of the cases. Fifty-five (68.7%) participants had the absence of rectal bleeding after 12 months of embolization. VAS and QL improved 4 points and 1.5 respectively after embolization. A total of 25/80 (31.3%) had a recurrence in rectal bleeding. Seventeen (21.3%) patients underwent a second embolization, and four patients (5%) were treated with open hemorrhoidectomy. No major complications were observed. Sixteen participants had minor complications. Subjective post-treatment symptom and QL surveys showed significant differences from the baseline survey. Likewise, the degree of satisfaction in the telephone survey at 12 months revealed a high degree of patient satisfaction (8.3±1.1). Conclusions: The present study demonstrates that CDHE is a feasible, well-tolerated, ambulatory, anal sphincter-sparing procedure for the treatment of internal hemorrhoids. Clinical relevance statement: CDHE is a simple procedure, well tolerated and accepted by patients, that preserves the anal sphincter and presents few complications when metal devices or microspheres are used as embolic agents. Key Points: • The technical success rate of CDHE, defined as the closure of all the SRA in their distal segment, was achieved 100% of all patients. However, a second embolization treatment was required since 21.25% of the patients experienced rectal bleeding. • Overall, CDHE's safety profile is acceptable. After the procedure and 1 year of follow-up, no significant complications were observed. • Encouraging clinical outcomes have demonstrated CDHE in individuals with hemorrhoids and mild prolapse Goligher grades I–III with persistent rectal bleeding. [ABSTRACT FROM AUTHOR]

In studying communicative signals, we can think of flexibility as a necessary correlate of creativity. Flexibility enables animals to find practical solutions and appropriate behaviors in mutable situations. In this study, we aimed to quantify the degree of flexibility in the songs of indris (Indri indri), the only singing lemur, using three different metrics: Jaro Distance, normalized diversity, and entropy. We hypothesized that the degree and the co-variation of the flexibility of indris singing together would vary according to their status and sex. We found that dominant females were more flexible than dominant males when concatenating elements into strings (element concatenation). The number of different elements in a song contribution normalized by the contribution length (contribution diversity) of dominant individuals positively co-varied for seven duetting pairs. Non-dominant individuals were more variable in element concatenation than dominant individuals, and they were more diverse in phrase type than dominant females. Independently from sex and status, individual contributions did not differ in entropy (a measure of the predictability of contributions). These results corroborate previous findings regarding the dimorphism by sex and by status of individual contributions to songs. Thus, they shed light on the presence and expression of flexibility in the behavior of a non-human primate species. Indeed, they potentially show an effect of social features in shaping vocal flexibility, which underlies many communication systems, including human language. We speculate that this degree of flexibility may account for creativity. [ABSTRACT FROM AUTHOR]

Abstract In the last century, vaccination has been the most effective medical intervention to reduce death and morbidity caused by infectious diseases. It is believed that vaccines save at least 2–3 million lives per year worldwide. Smallpox has been eradicated and polio has almost disappeared worldwide through global vaccine campaigns. Most of the viral and bacterial infections that traditionally affected children have been drastically reduced thanks to national immunization programs in developed countries. However, many diseases are not yet preventable by vaccination, and vaccines have not been fully exploited for target populations such as elderly and pregnant women. This review focuses on the state of the art of recent clinical trials of vaccines for major unmet medical needs such as HIV, malaria, TB, and cancer. In addition, we describe the innovative technologies currently used in vaccine research and development including adjuvants, vectors, nucleic acid vaccines, and structure‐based antigen design. The hope is that thanks to these technologies, more diseases will be addressed in the 21st century by novel preventative and therapeutic vaccines.

The paper presents a mechanical-based framework for the evaluation of local-scale seismic fragility curves. The approach is oriented to a seismic vulnerability assessment of unreinforced masonry buildings and makes use of basic exposure data easily obtained from survey or available in existing database. An efficient finite element model and static nonlinear analyses are employed to assess the structural behaviour. The mechanical-based fragility curves are evaluated using Monte Carlo simulations that allow to account for the uncertainties propagation. The proposed approach is tested on a case-study regarding the city centre of Cosenza, in southern Italy, using exposure information available from CARTIS database. [ABSTRACT FROM AUTHOR]

Anxiety disorders (ADs) represent the sixth leading cause of disability worldwide, resulting in a significant global economic burden. Over 50% of individuals with ADs do not respond to standard therapies, making the identification of more effective anxiolytic drugs an ongoing research priority. In this work, we review the preclinical literature concerning the effects of lysergic acid diethylamide (LSD) on anxiety-like behaviors in preclinical models, and the clinical literature on anxiolytic effects of LSD in healthy volunteers and patients with ADs. Preclinical and clinical findings show that even if LSD may exacerbate anxiety acutely (both in "microdoses" and "full doses"), it induces long-lasting anxiolytic effects. Only two randomized controlled trials combining LSD and psychotherapy have been performed in patients with ADs with and without life-threatening conditions, showing a good safety profile and persisting decreases in anxiety outcomes. The effect of LSD on anxiety may be mediated by serotonin receptors (5-HT1A/1B, 5-HT2A/2C, and 5-HT7) and/or transporter in brain networks and circuits (default mode network, cortico–striato–thalamo–cortical circuit, and prefrontal cortex-amygdala circuit), involved in the modulation of anxiety. It remains unclear whether LSD can be an efficacious treatment alone or only when combined with psychotherapy, and if "microdosing" may elicit the same sustained anxiolytic effects as the "full doses". Further randomized controlled trials with larger sample size cohorts of patients with ADs are required to clearly define the effective regimens, safety profile, efficacy, and feasibility of LSD for the treatment of ADs. [ABSTRACT FROM AUTHOR]

Nonlinear phenomena (NLP) in animal vocalizations arise from irregularities in the oscillation of the vocal folds. Various non-mutually exclusive hypotheses have been put forward to explain the occurrence of NLP, from adaptive to physiological ones. Non-human primates often display NLP in their vocalizations, yet the communicative role of these features, if any, is still unclear. We here investigate the occurrence of NLP in the song of a singing primate, the indri (Indri indri), testing for the effect of sex, age, season, and duration of the vocal display on their emission. Our results show that NLP occurrence in indri depends on phonation, i.e., the cumulative duration of all the units emitted by an individual, and that NLP have higher probability to be emitted in the later stages of the song, probably due to the fatigue indris may experience while singing. Furthermore, NLP happen earlier in the vocal display of adult females than in that of the adult males, and this is probably due to the fact that fatigue occurs earlier in the former because of a greater contribution within the song. Our findings suggest, therefore, that indris may be subjected to physiological constraints during the singing process which may impair the production of harmonic sounds. However, indris may still benefit from emitting NLP by strengthening the loudness of their signals for better advertising their presence to the neighboring conspecific groups. [ABSTRACT FROM AUTHOR]

Purpose: Pazopanib has promising antiangiogenetic activity in solid cancers. The investigator-initiated phase I/II trial evaluated the combination of Topotecan with Pazopanib in platinum-resistant or intermediate-sensitive recurrent ovarian cancer (ROC). Methods: Patients (≥ 18 years) with first or second recurrence were enrolled in this multicentre open-label trial. Phase I analysed Topotecan 4 mg/m2 (day 1, 8, 15, ever 28 days) for six cycles to identify the maximum tolerated dose (MTD) of Pazopanib added in a dose-escalating scheme with 400 mg starting dose. The phase II analysed safety and efficacy aspects. For all patients with clinical remission a maintenance with Pazopanib until progression was allowed. This trial is registered with ClinicalTrials.gov, number NCT 01600573. Results: Between June 2012 and February 2017, 11 patients were enrolled in the phase I, and 50 patients in the phase II study. The MTD of Pazopanib was determined by 400 mg/daily. Haematological and liver toxicities determined the dose limiting toxicities (DLT) and the most common grade 3–4 adverse events: leucopenia (25%), neutropenia (22%), thrombocytopenia (19%), accumulation of cholestatic (20%) and hepatocellular damage (15%), which often caused dose modifications, but no new life-threatening events. Overall response was 16% and clinical benefit rate 68%. Median progression-free survival (PFS) was 3.5 months (95% CI 2.0—5.0). Due to early progression only 20% of the patients were able to start with maintenance treatment. Conclusion: The combination of pazopanib and weekly topotecan is feasible, resulting in a manageable haematological and liver toxicity, but despite its encouraging response rate, was not associated with a significant survival benefit. [ABSTRACT FROM AUTHOR]

In vitro ovarian cortical tissue culture, followed by culture of isolated secondary follicles, is a promising future option for production of mature oocytes. Although efforts have been made to improve the culture outcome by changing the medium composition, so far, most studies used static culture systems. Here we describe the outcome of 7 days cultures of bovine and human ovarian cortical tissue in a dynamic system using a novel perifusion bioreactor in comparison to static culture in conventional and/or gas permeable dishes. Findings show that dynamic culture significantly improves follicle quality and viability, percentage and health of secondary follicles, overall tissue health, and steroid secretion in both species. Model predictions suggest that such amelioration can be mediated by an enhanced oxygen availability and/or by fluid-mechanical shear stresses and solid compressive strains exerted on the tissue. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the theoretical hydrodynamic effects of a single or a double XEN 45 Gel Stent (XEN45) implant in glaucomatous eyes. Methods: A prospective non-randomized clinical study on 63 glaucomatous eyes of 63 patients. The preoperative intraocular pressure (IOP) values after 14 days of medical therapy washout was correlated to the postoperative IOP values 7 and 45 days after the implant of a XEN45. A mathematical model based on the Hagen-Poiseuille law was designed to assess the residual aqueous humor outflow (AHO) facility in glaucomatous eyes in function of the postoperative IOP reduction. Using XEN45 as unit of measurement, we transformed through equations the residual preoperative AHO in XEN45 equivalent in order to establish theoretical number of stents needed to reach the target IOP. Results: The mean preoperative washout IOP was 28.9 ± 5.4 mmHg, after 7 and 45 days the mean postoperative IOP was 12.6 ± 4.3 and 15.3 ± 4.4 mmHg, respectively (p < 0.001). A significant positive correlation was found between preoperative and postoperative IOP values. We obtained a mathematical relationship to estimate the theoretical number of XEN45 stents needed to reach the target IOP. Conclusion: The basal IOP (after medical therapy washout) is a predictive factor for the surgical success after a XEN45 implant. Establishing the residual preoperative AHO it is possible to predict the theoretical number of stents to implant. A double XEN45 implant could be considered a possible further tool to reach the target IOP in patients with severe AHO deficiency. [ABSTRACT FROM AUTHOR]

By reference to a sample of 173 emerging adult seminarians in South Italy, this study evaluates the influence of attachment to one's parents and peers on identity development and well-being in seminarians. The statistical analysis (PLS-PM) reports that secure attachment to one's mother and secure attachment to a peer are positively associated with identity and well-being. No such association is found with attachment to one's father. Attachment to one's mother loses its association with identity during the shift from the freshmen to the senior group and is replaced by attachment with one's peers. Both attachment relationships lose their associations with well-being between these groups. Our results demonstrate that attachment to one's peers becomes the most relevant relationship, thus supporting this specific form of relationship among seminarians. [ABSTRACT FROM AUTHOR]

Purpose: Evaluation of a novel ultrasound-simulation-app for training fetal echocardiography as a possible useful addition for students, residents and specialist doctors. Furthermore, comparison to a conventional learning-method with special attention on orientation and recognition of physiological structures. Methods: Prospective two-arm study with the participation of 226 clinical students. 108 students were given an extract from a textbook on fetal echocardiography (PDF-group, n = 108) for 30 min to study. 118 students were able to use the new ultrasound-simulator-app (Simulator-group, n = 118) to learn for 30 min. The knowledge of the students was examined both before and after the learning-period by having them identify sonographic structures in videos using single-choice selection. Results: There were no significant differences between the two groups regarding age (p = 0.87), gender (p = 0.28), and the number of previously performed ultrasound-examinations (p = 0.45). In the Simulator-group, there was a significantly higher learning effect regarding the proportion of students with an increase of correct answers in the video test examination (p = 0.005). At the end of learning, the students in the Simulator-group needed significantly less time to display the structures in the app's simulation (median initially 10.9 s vs. 6.8 s at the end; p < 0.001). Conclusions: The novel ultrasound-simulation-app seems to be a useful addition and improvement to ultrasound training. Previous difficulties such as simultaneously having patients, ultrasound-machines, and professors at disposal can thus be avoided. This means that another important step towards remote learning can be taken, which has been proven increasingly essential lately, due to the COVID-19 pandemic. [ABSTRACT FROM AUTHOR]

Contrary to spontaneous yawning, yawn contagion occurs when yawning in a subject (responder) is elicited by the yawns of others (triggers). Yawn contagion has been associated with inter-individual synchronisation, activity coordination and possibly emotional contagion, based on the perception–action mechanism. We collected data on yawn contagion and grooming and verified—for the first time—yawn contagion presence and modulating factors in a wild strepsirhine. Specifically, we considered the diurnal lemur Indri indri (inhabiting Maromizaha rainforest, eastern Madagascar), which lives in socially cohesive family units. We recorded 613 yawning events involving 28 individuals and found that yawn contagion was present in the indris (with the best predictor for an individual to yawn at a given time of day was observing another group member yawning) and that it was positively influenced by grooming levels (but not by the spatial distance) between trigger and responder. Age and sex had no significant relationship with yawn contagion likelihood. Because yawn contagion has been found in different mammalian species regardless of their phylogenetic closeness, this study, reporting the phenomenon in a lemur species with highly cohesive behavioural pattern and able to emit coordinated vocal displays, adds a valuable piece to the investigation of the pressures that may have favoured yawning as a (possibly emotional) communicative cue during evolution. Significance statement: Yawn contagion is associated with inter-individual synchronisation and activity coordination. While this behaviour is often investigated in apes, its presence in lemurs is debated. Here, we explored presence and modulating factors of yawn contagion in Indri indri, a critically endangered primate living in small family units where individuals show coordinated circadian rhythms and a highly cohesive behavioural pattern. We first demonstrated the presence of yawn contagion in wild indris where, in line with the high degree of behavioural synchrony showed by the individuals within a group, it may possibly indicate a transmission of physiological states. We also demonstrated the association of contagion with grooming rates, but not with the spatial proximity between triggers and responders, nor with their sex and age, pointing at social closeness as the most likely modulating factor. [ABSTRACT FROM AUTHOR]

An editorial titled "Interventional Radiology: A True Medical Specialty" appeared in the medical journal Cardiovascular and Interventional Radiology. The editorial argues for the establishment of interventional radiology as a separate specialty from diagnostic radiology. The authors, Professor Andreas Adam and Dr. Lizbeth Kenny, highlight the potential of interventional radiology but also acknowledge current shortcomings, such as identity confusion and a focus on technical rather than clinical practice. They emphasize the need for autonomy and adapted training programs to meet clinical requirements and provide comprehensive patient care. The editorial underscores the urgent need for interventional radiology to establish itself as a primary specialty to fully realize its potential and better serve patients. [Extracted from the article]

It is still continuously debated whether the low-dose/dose-rate (LDR) of ionizing radiation represents a hazard for humans. Model organisms, such as fruit flies, are considered valuable systems to reveal insights into this issue. We found that, in wild-type Drosophila melanogaster larval neuroblasts, the frequency of Chromosome Breaks (CBs), induced by acute γ-irradiation, is considerably reduced when flies are previously exposed to a protracted dose of 0.4 Gy delivered at a dose rate of 2.5 mGy/h. This indicates that this exposure, which is associated with an increased expression of DNA damage response proteins, induces a radioadaptive response (RAR) that protects Drosophila from extensive DNA damage. Interestingly, the same exposure reduces the frequency of telomere fusions (TFs) from Drosophila telomere capping mutants suggesting that the LDR can generally promote a protective response on chromatin sites that are recognized as DNA breaks. Deep RNA sequencing revealed that RAR is associated with a reduced expression of Loquacious D (Loqs-RD) gene that encodes a well-conserved dsRNA binding protein required for esiRNAs biogenesis. Remarkably, loss of Loqs mimics the LDR-mediated chromosome protection as it decreases the IR-induced CBs and TFs frequency. Thus, our molecular characterization of RAR identifies Loqs as a key factor in the cellular response to LDR and in the epigenetic routes involved in radioresistance. Chronic low y-radiation exposure to Drosophila cells decreases chromosome breaks induced by high-dose irradiation and telomere dysfunction by reducing the esiRNA biogenesis factor Loquacious D. [ABSTRACT FROM AUTHOR]

Deforestation around the world is a major threat to primates. Understanding primate species' habitat and dietary requirements is critical in creating effective conservation management plans. Indri indri, a Critically Endangered lemur species from Madagascar's eastern rainforests, has a diet dominated by leaves. We conducted a long-term study of I. indri feeding behavior in Maromizaha Protected Area by collecting over 4000 hours of observational data on six habituated groups from 2011–2019. Our specific objectives were to: 1) characterize the habitat of the study groups, 2) identify the availability of leaves, fruits, and flowers, 3) provide a description of the general diet of I. indri including variation therein, 4) describe a newly observed regurgitation and re-ingestion behavior, and 5) perform phytochemical analyses of the leaves and fruits which were likely causing the regurgitation and re-ingestion. Areas of similar topography generally had similar forest structure. Phenological monitoring of 18 botanical plots located in the I. indri territories showed that the availability of young leaves, fruits, and flowers varied seasonally and was impacted by damage from a cyclone in February 2012. All groups were mainly folivorous but showed some annual variation in the proportion of the diet devoted to fruit. Leaves and fruits consumed before regurgitation and re-ingestion was observed contained hydrolysable and condensed tannins, which may explain the presence of the behavior. In conclusion, this study provides important natural history data on the behavioral flexibility of I. indri to inform their conservation. [ABSTRACT FROM AUTHOR]

In mammals, olfactory communication plays an essential role in territorial and mating dynamics. Scent depositions in various species, including lemurs, can be placed via marking or overmarking (marking over previous depositions). We focused on the role that marking and overmarking play in territorial defence and intrasexual competition. We investigated these aspects in diademed sifaka (Propithecus diadema) in the primary rainforest of Maromizaha (eastern Madagascar). We collected scent marking data for five groups from April to November 2018 and from May to December 2019. We aimed to understand whether the lemurs deposited scent marks homogeneously across the home range and whether sex, rank, and occurrence of intergroup encounters affected the lemur's deposition rate. We also asked whether males overmarked adult females more often than other depositions, and the marking and overmarking rates changed between the migration and non-migration seasons. We found that scent marking was performed higher in peripheral and overlapping areas than in the home range central areas. In addition, males had higher scent marking rates, but intergroup encounters did not affect deposition rates. Males showed higher rates of overmarking and primarily targeted dominant females' depositions, particularly during the "migration" season (including premating and mating seasons). Our findings suggest a border-marking strategy in Propithecus diadema. More frequent scent marking in the "migration" season suggests intrasexual competition in males. Our results suggest that marking is associated with territorial and resource defence, suggesting that it plays a role in monopolizing females using a mate-guarding strategy and may also serve for males' self-advertisement to females and subordinate depositors. [ABSTRACT FROM AUTHOR]

Strepsirrhine vocalisations are extraordinarily diverse and cross-species comparisons are needed to explore how this variability evolved. We contributed to the investigation of primate acoustic diversity by comparing the vocal repertoire of two sympatric lemur species, Propithecus diadema and Indri indri. These diurnal species belong to the same taxonomic family and have similar activity patterns but different social structures. These features make them excellent candidates for an investigation of the phylogenetic, environmental, and social influence on primate vocal behavior. We recorded 3 P. diadema groups in 2014 and 2016. From 1,872 recordings we selected and assigned 3814 calls to 9 a priori call types, on the basis of their acoustic structure. We implemented a reproducible technique performing an acoustic feature extraction relying on frequency bins, t-SNE data reduction, and a hard-clustering analysis. We first quantified the vocal repertoire of P. diadema, finding consistent results for the 9 putatively identified call types. When comparing this repertoire with a previously published repertoire of I. indri, we found highly species-specific repertoires, with only 2% of the calls misclassified by species identity. The loud calls of the two species were very distinct, while the low-frequency calls were more similar. Our results pinpoint the role of phylogenetic history, social and environmental features on the evolution of communicative systems and contribute to a deeper understanding of the evolutionary roots of primate vocal differentiation. We conclude by arguing that standardized and reproducible techniques, like the one we employed, allow robust comparisons and should be prioritized in the future. [ABSTRACT FROM AUTHOR]

On March 14, 2020 one of the strictest confinements in Europe was imposed on the citizens of Spain. The online tool for parents, iCygnus, was designed to reduce the psychological impact generated by the pandemic on the child population (2–12 years of age) through automatic recommendations to parents based on individual responses about their parenting styles and their child's characteristics. The profiles of the 710 families indicate a higher prevalence of internalizing and externalizing behavior problems in children, as well as a relationship between punitive parenting in families where the parents lost their jobs due to the coronavirus disease (COVID-19). The usefulness of the help offered by iCygnus was evaluated after 6 weeks, and almost 80% of the families indicated that they used the recommendations and that they helped them in their relationship with their children. [ABSTRACT FROM AUTHOR]

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Background: Anthracycline/cyclophosphamide-taxane-containing chemotherapy (AC-T) is the standard of care in the adjuvant treatment of HER2-negative early breast cancer (EBC), but recent studies suggest omission of anthracyclines for reduced toxicity without compromising efficacy. Methods: Based on individual patient data (n = 5924) pooled from the randomised Phase III trials PlanB and SUCCESS C, we compared disease-free survival (DFS) and overall survival (OS) between intermediate to high-risk HER2-negative EBC-patients treated with either six cycles of docetaxel/cyclophosphamide (TC6) or an AC-T regime using univariable and adjusted multivariable Cox regression models. Results: AC-T conferred no significant DFS or OS advantage in univariable (DFS: hazard ratio (HR) for TC vs. AT 1.05, 95% confidence interval (CI): 0.89–1.24, P = 0.57; OS: HR 1.00, 95% CI: 0.80–1.26, P = 1.00) and adjusted multivariable analysis (DFS: HR 1.01, 95% CI: 0.86–1.19, P = 0.91; OS: HR 0.97, 95% CI: 0.77–1.22, P = 0.79). Patients receiving TC6 had significantly fewer grade 3–4 adverse events. Exploratory subgroup analysis showed that AC-T was associated with significantly better DFS and OS in pN2/3 patients, specifically in those with lobular histology. Conclusion: For most patients with HER2-negative EBC, AC-T is not associated with a survival benefit compared to TC6. However, patients with lobular pN2/pN3 tumours seem to benefit from anthracycline-containing chemotherapy. [ABSTRACT FROM AUTHOR]

Purpose: The relation between OSAS and eye diseases is well known in adults, while very few and contradictory data can be found regarding paediatric ages. The aim of this study is to explore the early corneal, macular and optic nerve changes in paediatric patients with OSAS. Methods: Prospective study that enrolled children aged ≥ 4 years referred to the Paediatric Pneumology Clinic in Verona for suspected obstructive sleep apnoea syndrome (OSAS) and investigated with the overnight respiratory polygraphy. Patients with apnoea–hypopnea index (AHI) > 1 were classified as OSAS, while those with AHI < 1 were classified non-OSAS. All patients underwent comprehensive eye examination including slit lamp, refraction, intraocular pression (Goldman applanation tonometry), corneal tomography (corneal astigmatism, corneal keratometry at the apex, surface asymmetry index, central corneal thickness and thinnest corneal thickness) and optical coherence tomography (central macular thickness, macular volume and retinal nerve fibre layer). Results: Seventy-two children were enrolled in the study. The overall prevalence of OSAS was 48.6%. Statistically significant differences were found between OSAS and non-OSAS group for corneal asymmetry (0.9 ± 0.5 and 0.6 ± 0.3, respectively; p = 0.02), thinnest corneal thickness (551.8 ± 33.9 and 563.7 ± 32.5; p = 0.04), average retinal nerve fibre layer (102.8 ± 10.5 µm and 98.1 ± 12.3 µm; p = 0.012) and in nasal quadrant (76.2 ± 15.4 µm and 66.5 ± 12.6 µm; p = 0.0002). Conclusions: A comprehensive eye examination with corneal and optic nerve imaging showed early corneal and optic nerve changes in children newly diagnosed with OSAS. These could be prelude of the known ocular manifestations associated with OSAS in adult patients. [ABSTRACT FROM AUTHOR]

This document, titled "The IR Platypus," is a letter published in the journal CardioVascular & Interventional Radiology. The author reflects on a conversation with a Mexican colleague about the challenges and unique nature of their work in Interventional Radiology (IR). They compare IR to the peculiar platypus, highlighting the dichotomy between their role as radiologists and their surgical-like practice. The author expresses frustration with the lack of understanding and recognition of their profession, emphasizing the importance of validation from their peers and the medical community. They also mention a recent discovery about the platypus that brings them solace. The document concludes with funding and conflict of interest declarations. [Extracted from the article]

We deal with complex spatial diffusion equations with time-fractional derivative and study their stochastic solutions. In particular, we complexify the integral operator solution to the heat-type equation where the time derivative is replaced with the convolution-type generalization of the regularized Caputo derivative. We prove that this operator is solution of a complex time-fractional heat equation with complex spatial variable. This approach leads to a wrapped Brownian motion on a circle time-changed by the inverse of the related subordinator. This time-changed Brownian motion is analyzed and, in particular, some results on its moments, as well as its construction as weak limit of continuous-time random walks, are obtained. The extension of our approach to the higher dimensional case is also provided. [ABSTRACT FROM AUTHOR]

Purpose: Only a few studies are available on dose-related effects of sacubitril/valsartan (angiotensin receptor neprilysin inhibition (ARNI)) in real-life patients with heart failure and reduced ejection fraction (HFrEF). We sought to investigate clinical and functional effects in real-life HFrEF patients receiving ARNI at a different cumulative dose. Methods: This was an observational study in consecutive outpatients admitted for HFrEF from October 2017 to June 2019. The PARADIGM criteria were needed for enrolment. ARNI was uptitrated according to blood pressure, drug tolerability, renal function and kaliemia. At least 10-month follow-up was required in each patient. Clinical assessment, Kansas City Cardiomyopathy Questionnaire (KCCQ) score, 6-min walk test and strain echocardiography were performed in each patient on a regular basis during the observational period. At the end of the study, patients were divided into two groups based on the median yearly dose of the ARNI medication. Results: A total of 90 patients, 64 ± 11 years, 82% males, were enrolled. The cut-off dose was established in 75 mg BID, and the study population was divided into group A (≤ 75 mg), 52 patients (58%), and group B (> 75 mg), 38 patients (42%). The follow-up duration was 12 months (range 11–13). NYHA class, KCCQ score and 6MWT performance ameliorated in both groups, with a quicker time to benefit in group B. The proportion of patients walking > 350 m increased from 21 to 58% in group A (p < 0.001), and from 29 to 82% in group B (p < 0.001). A positive effect was also disclosed in the left ventricular remodelling, strain deformation and diastolic function. Conclusion: One-year ARNI treatment was effective in our real-life HFrEF patient population, leading to clinical and functional improvement in both study groups, slightly greater and with a shorter time to benefit in group B. [ABSTRACT FROM AUTHOR]

A clear evidence on the benefits of somatostatin analogues (SA) on liver outcome in patients affected by polycystic liver disease is still lacking. We performed a meta-analysis of RCTs and a trial sequential analysis (TSA) evaluating the effects of SA in adult patients with polycystic liver disease on change in liver volume. As secondary outcome, we evaluated the effects on quality of life as measured by SF36-questionnaire. Six RCTs were selected with an overall sample size of 332 adult patients with polycystic liver disease (mean age: 46 years). Mean liver volume at baseline was 3289 ml in SA group and 3089 ml in placebo group. Overall, unstandardized mean difference in liver volume was − 176 ml (95%CI, − 406, 54; p < 0.133). Heterogeneity was low (I2:0%, p < 0.992). However, we performed a moderator analysis and we found that a higher eGFR significantly correlates to a more pronounced effect of SA on liver volume reduction (p = 0.036). Cumulative Z-curve in TSA did not reach either significance and futility boundaries or required information size. Three RCTs have evaluated Quality of life parameters measured by SF36-QOL questionnaire for a total of 124 patients; no significant difference was found on the effect of SA on QOL parameters when compared with placebo. The present meta-analysis revealed a potential effect of SA on reduction of liver volume and quality of life parameters, but results did not reach a statistical significance. These data could be explained by the need of further studies, as demonstrated through TSA, to reach an adequate sample size to confirm the beneficial outcomes of SAs treatment. [ABSTRACT FROM AUTHOR]

Environmental pollution plays an important role in amphibian population decline. Contamination with endocrine disrupting chemicals (EDCs) is particularly worrying due to their capacity to adversely affect organisms at low doses. We hypothesized that exposure to EDCs such as 4-nonylphenol (NP) and cyproterone acetate (CPA) could trigger responses in the liver and gonads, due to toxic and endocrine disrupting effects. Growth rate may also be impaired by contamination. We investigated sublethal effects of a 28-day exposure to three different concentrations of NP and CPA on liver pigmentation, gonadal morphology, body mass, and length of tadpoles and juveniles Lithobates catesbeianus. Liver pigmentation and the gonadal morphologies of treated tadpoles did not differ from control, but growth rate was impaired by both pollutants. Juveniles treated with 10 μg/L NP and 0.025 and 0.25 ng/L CPA displayed increased liver melanin pigmentation, but gonadal morphologies, sex ratios, and body mass were not affected after treatments. The increase in liver pigmentation may be related to defensive, cytoprotective role of melanomacrophages. The decreased growth rate in tadpoles indicates toxic effects of NP and CPA. Thus, contamination with NP and CPA remains a concern and sublethal effects of different dosages of the compounds on native species should be determined. [ABSTRACT FROM AUTHOR]

Background: As the population at risk for pelvic nodal involvement remains poorly described, the role of pelvic lymphadenectomy (LAE) in vulvar squamous cell cancer (VSCC) has been a matter of discussion for decades. Methods: In the AGO-CaRE-1 study, 1618 patients with International Federation of Gynecology and Obstetrics (FIGO) stage IB or higher primary VSCC treated at 29 centers in Germany between 1998 and 2008 were documented. In this analysis, only patients with pelvic LAE (n = 70) were analyzed with regard to prognosis and correlation between inguinal and pelvic lymph node involvement. Results: The majority of patients had T1b/T2 tumors (n = 47; 67.1%), with a median diameter of 40 mm (2–240 mm); 54/70 patients (77.1%) who received pelvic LAE had positive groin nodes. For 42 of these 54 patients, the number of affected groin nodes had been documented as a median of 3; 14/42 (33.3%) of these patients had histologically confirmed pelvic nodal metastases (median number of affected pelvic nodes 3 [1–12]). In these 14 patients, the median number of affected groin nodes was 7 (1–30), with a groin metastases median maximum diameter of 42.5 mm (12–50). Receiver operating characteristic analysis showed an area under the curve of 0.85, with 83.3% sensitivity and 92.6% specificity for the prediction of pelvic involvement in cases of six or more positive groin nodes. No cases of pelvic nodal involvement without groin metastases were observed. Prognosis in cases of pelvic metastasis was poor, with a median progression-free survival of only 12.5 months. Conclusion: For the majority of node-positive patients with VSCC, pelvic nodal staging appears unnecessary since a relevant risk for pelvic nodal involvement only seems to be present in highly node-positive disease. [ABSTRACT FROM AUTHOR]

The aim of this paper is to introduce an adaptive penalized estimator for identifying the true reduced parametric model under the sparsity assumption. In particular, we deal with the framework where the unpenalized estimator of the structural parameters needs simultaneously multiple rates of convergence (i.e., the so-called mixed-rates asymptotic behavior). We introduce a bridge-type estimator by taking into account penalty functions involving ℓ q norms (0 < q ≤ 1). We prove that the proposed regularized estimator satisfies the oracle properties. Our approach is useful for the estimation of stochastic differential equations in the parametric sparse setting. More precisely, under the high-frequency observation scheme, we apply our methodology to an ergodic diffusion and introduce a procedure for the selection of the tuning parameters. Furthermore, the paper contains a simulation study as well as a real data prediction in order to assess about the performance of the proposed bridge estimator. [ABSTRACT FROM AUTHOR]

Introduction: Large translational research projects may contribute to further progress in cancer treatment by exploring molecular biology, immunologic approaches and identification of new prognostic and predictive factors. Therefore, the BRandOBio-project combines a clinical registry for collection of patient and tumor characteristics with a biobank comprising tumor and liquid biopsies. In addition, sociodemographic, environmental and lifestyle factors of included patients with primary newly diagnosed breast or ovarian cancer, other rare malignant ovarian tumors or gestational trophoblastic disease are prospectively collected.Methods: The target population includes the German "Alb-Allgäu-Bodensee Region" which constitutes the outreach area of the University Hospital Ulm with affiliated academic centers and private practices. Clinical data combined with primary tumor tissue samples and longitudinal repeatedly collected blood samples [before, 6 (in high-risk situations), 12, 36 and 60 months after treatment and at relapse] will be acquired from more than 4000 patients within the next years. Standardized questionnaires are given to patients of the University Hospital Ulm and eight selected external sites for assessing life style and cancer risk factors. Concomitantly, storage of paraffin-embedded tumor samples as well as liquid biopsy samples will allow translational research projects, for example in terms of investigating circulating DNA and germ line DNA from cell pellets.Results: Starting in January 2016 at the University Hospital Ulm, 19 additional external sites started recruiting patients in March 2017. As of September 15th 2019, 2151 patients with newly diagnosed cancers could be recruited (2044 breast cancer; 107 ovarian cancer). Nearly all patients provided biological samples (tumor and liquid biopsy) and about 80% returned the standardized questionnaire. After 1 year follow-up, blood samples were available from more than 80% of the participating patients.Conclusions: The BRandO BIO study is a large prospective cohort study with integrated comprehensive biobank and evaluation of sociodemographic and life style factors of gynecological cancer patients in a well-defined geographical area in the South West of Germany. Continuous high patient recruitment and stable rates over 80% for returned questionnaires as well as for repeated blood sampling show high acceptance of the BRandO study program and confirms feasibility of the project. [ABSTRACT FROM AUTHOR]

Purpose: Lymph node metastases significantly worsen the prognosis in cervical carcinoma. Risk factors-pathological and patient related-could select patients at high risk for lymph node involvement.Methods: This retrospective analysis was performed by analyzing data from patients with cervical carcinoma treated between 2000 and 2017 at the Department of Obstetrics and Gynecology of the University Hospital Ulm.Results: In total, 261 patients with cervical carcinoma (International Federation of Gynecology and Obstetrics (FIGO) stage IA-IIB) and lymphadenectomy with at least 10 removed lymph nodes were available for analysis. Overall, 86 (33.0%) patients had lymph node metastases; 73 patients had pelvic lymph node metastases only and 13 patients had both pelvic and paraaortic lymph node metastases. Lymph node metastases were found most often in the region of the external iliac artery and obturator fossa, with 57.0% and 54.7% of all 86 node-positive patients, respectively. Univariable analyses showed that presence of lymph node metastases was significantly associated with both preoperative FIGO stage (p = 0.001) and final pathological tumor stage (p < 0.001), status of resection margin (p = 0.002), lymphovascular space invasion (LVSI), (p < 0.001) and vascular space invasion, (p < 0.001). In a multivariable logistic regression model with presence of lymph node metastases (yes/no) as binary response variable, only LVSI (p < 0.001) and body mass index (BMI), (p = 0.035) remained as significant independent predictors of lymph node involvement. Subgroup analyses showed that LVSI was a significant predictive factor for lymph node involvement in patients with a preoperatively assessed FIGO stage < IIB (p < 0.001), but not for patients with a preoperatively assessed FIGO stage ≥ IIB (p = 0.122).Conclusions: The risk factor LVSI should play an important role in deciding whether an individualized therapy concept is based on escalating or deescalating treatment. In future, the sentinel concept could reduce morbidity and at the same time provide an important prognostic assessment for a subset of cervical cancer patients. [ABSTRACT FROM AUTHOR]

Background: Pelvic exenterations are a last resort procedure for advanced gynecologic malignancies with elevated risks in terms of patients' morbidity.Methods: This single-center analysis reports surgical details, outcome and survival of all patients treated with exenteration for non-ovarian gynecologic malignancies at our university hospital during a 13-year time period. We collected data regarding patients and tumor characteristics, surgical procedures, peri- and postoperative management, transfusions, complications, and analyzed the impact on survival outcomes.Results: We identified 37 patients between 2005 and 2013 with primary or relapsed cervical cancer (59.5%), vulvar cancer (24.3%) or endometrial cancer (16.2%). Median age was 60 years and most patients (73%) had squamous cell carcinomas. Median progression-free survival was 26.2 months and median overall survival was 49.9 months. The 5-year survival rates were 34.4% for progression-free survival and 46.4% for overall survival. There were no significant differences in progression-free survival and overall survival with regard to disease entity. Patients with tumor at the resection margins (R1) had a nearly significantly worse progression-free survival (median: 28.5 vs. 7.3 months, HR 2.59, 95% CI 0.98-6.88, p = 0.056) and a significantly worse overall survival (median: not reached vs. 10.9 months, HR 4.04, 95% CI 1.40-11.64, p = 0.010) compared to patients with complete tumor resection (R0). In addition, patients without lymphovascular space invasion had a significantly better progression-free survival (p = 0.017) and overall survival (p = 0.034) then patients with lymphovascular space invasion. We observed complications in 14 patients (37.8%), 10 of those were classified as Clavien-Dindo 3 or 4. There was a trend to worse progression-free survival in patients that suffered complications (p = 0.052). Median total amount of transfused blood products was 4 (range 0-20).Conclusion: Pelvic exenteration is a procedure that provides substantial progression-free survival and overall survival improvement and-in selected patients-can even achieve cure in otherwise hopeless clinical situations. Patients need to be offered earnest counseling for sufficient informed consent with realistic expectations what to expect. [ABSTRACT FROM AUTHOR]