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Ovarian cancer (OC) patients develop ascites, an accumulation of ascitic fluid in the peritoneal cavity anda sign of tumour dissemination within the peritoneal cavity. This body fluid is under-researched, mainly regarding the ascites formed during tumour progression that have no diagnostic value and, therefore, are discarded. We performed a discovery proteomics study to identify new biomarkers in the ascites supernatant of OC patients. In this preliminary study, we analyzed a small amount of OC ascites to highlight the importance of not discarding such biological material during treatment, which could be valuable for OC management. Our findings reveal that OC malignant ascitic fluid (MAF) displays a proliferative environment that promotes the growth of OC cells that shift the metabolic pathway using alternative sources of nutrients, such as the cholesterol pathway. Also, OC ascites drained from patients during treatment showed an immunosuppressive environment, with up-regulation of proteins from the signaling pathways of IL-4 and IL-13 and down-regulation from the MHC-II. This preliminary study pinpointed a new protein (Transmembrane Protein 132A) in the OC context that deserves to be better explored in a more extensive cohort of patients’ samples. The proteomic profile of MAF from OC patients provides a unique insight into the metabolic kinetics of cancer cells during disease progression, and this information can be used to develop more effective treatment strategies.

I argue for a transformative revival or actualization of the very core of an integrative, methodologically secured form of intellect-mystical asceticism. This approach draws on traditional sources that are re-examined from a systematic—synthetic and transcultural—philosophical perspective and in light of the multi-civilizational global environment of the 21st century. The main traditional points of reference in this paper are provided by Nicolaus de Cusa and Ibn Sīnā, and I refer to a few others, such as Attar of Nishapur, in passing. I begin by developing a basic concept of intellect-mystical asceticism. It is distinguished from mystification, science, scientism, and modes of everyday communication and cognition. Then, I make the case for an updated, transcultural approach to intellect-mysticism that can foster the internal (social) and external (environmental) reintegration of the human noosphere and technosphere in future planetary development. In this context, a modern intellect-mystical philosophical notion of “knowing non-knowing” (wissendes Nichtwissen, docta ignorantia) is developed. It is inspired by Nicolaus de Cusa and contextualized from a systematic transcultural angle at the same time. Finally, I discuss the problem of the practical, or rather ascetic, realization of the related possibilities of intellect-mystical self-enfolding. Here, the preceding steps of the reflection are mapped onto an outline regarding distinct developmental stages of such a transformative intellect-mystical practice in Ibn Sīnā’s Remarks and Admonitions (al-Ishārāt wat-Tanbīhāt).

Biogenic polyamines are ubiquitous compounds. Dysregulation of their metabolism is associated with the development of various pathologies, including cancer, hyperproliferative diseases, and infections. The canonical pathway of polyamine catabolism includes acetylation of spermine and spermidine and subsequent acetylpolyamine oxidase (PAOX)-mediated oxidation of acetylpolyamines (back-conversion) or their direct efflux from the cell. PAOX is considered to catalyze a non-rate-limiting catabolic step. Here, we show that PAOX transcription levels are extremely low in various tumor- and non-tumor cell lines and, in most cases, do not change in response to altered polyamine metabolism. Its enzymatic activity is undetectable in the majority of cell lines except for neuroblastoma and low passage glioblastoma cell lines. Treatment of A549 cells with N1,N11-diethylnorspermine leads to PAOX induction, but its contribution to polyamine catabolism remains moderate. We also describe two alternative enzyme isoforms and show that isoform 4 has diminished oxidase activity and isoform 2 is inactive. PAOX overexpression correlates with the resistance of cancer cells to genotoxic antitumor drugs, indicating that PAOX may be a useful therapeutic target. Finally, PAOX is dispensable for the replication of various viruses. These data suggest that a decrease in polyamine levels is achieved predominantly by the secretion of acetylated spermine and spermidine rather than by back-conversion.

Hepatitis C virus (HCV) is an oncogenic virus that causes chronic liver disease in more than 80% of patients. During the last decade, efficient direct-acting antivirals were introduced into clinical practice. However, clearance of the virus does not reduce the risk of end-stage liver diseases to the level observed in patients who have never been infected. So, investigation of HCV pathogenesis is still warranted. Virus-induced changes in cell metabolism contribute to the development of HCV-associated liver pathologies. Here, we studied the impact of the virus on the metabolism of polyamines and proline as well as on the urea cycle, which plays a crucial role in liver function. It was found that HCV strongly suppresses the expression of arginase, a key enzyme of the urea cycle, leading to the accumulation of arginine, and up-regulates proline oxidase with a concomitant decrease in proline concentrations. The addition of exogenous proline moderately suppressed viral replication. HCV up-regulated transcription but suppressed protein levels of polyamine-metabolizing enzymes. This resulted in a decrease in polyamine content in infected cells. Finally, compounds targeting polyamine metabolism demonstrated pronounced antiviral activity, pointing to spermine and spermidine as compounds affecting HCV replication. These data expand our understanding of HCV’s imprint on cell metabolism.

Vocational interest inventories play an important role in supporting adolescents and young adults in their vocational choice. However, existing verbal and pictorial questionnaires have limitations regarding the complexity, abstraction level, and ambiguity of the item material. The presented research attempts to overcome these limitations by developing a new pictorial questionnaire. Study 1 describes the construction process of the Nonverbal Vocational Interest Scale (NVIS) and its psychometric properties, evaluation, and construct validation. Data from N = 363 adolescents and young adults in lower secondary school and vocational training centres were considered. Study 2 was conducted to confirm convergent and discriminant validity. N = 237 adolescents and young adults completed the revised form of the NVIS and the Photo-Interest-Inventory (F-I-T). The results confirm that the NVIS is a reliable and valid computer-based instrument for assessing vocational interests. Limitations and implications for further research and use in vocational training and counselling settings are discussed.

Ovarian cancer is a highly lethal form of gynecological cancer. This disease often goes undetected until advanced stages, resulting in high morbidity and mortality rates. Unfortunately, many patients experience relapse and succumb to the disease due to the emergence of drug resistance that significantly limits the effectiveness of currently available oncological treatments. Here, we discuss the molecular mechanisms responsible for resistance to carboplatin, paclitaxel, polyadenosine diphosphate ribose polymerase inhibitors, and bevacizumab in ovarian cancer. We present a detailed analysis of the most extensively investigated resistance mechanisms, including drug inactivation, drug target alterations, enhanced drug efflux pumps, increased DNA damage repair capacity, and reduced drug absorption/accumulation. The in-depth understanding of the molecular mechanisms associated with drug resistance is crucial to unveil new biomarkers capable of predicting and monitoring the kinetics during disease progression and discovering new therapeutic targets.

Decline of mitochondrial function is a hallmark of cellular aging. To counteract this process, some cells inherit mitochondria asymmetrically to rejuvenate daughter cells. The molecular mechanisms that control this process are poorly understood. Here, we made use of matrix-targeted D-amino acid oxidase (Su9-DAO) to selectively trigger oxidative damage in yeast mitochondria. We observed that dysfunctional mitochondria become fusion-incompetent and immotile. Lack of bud-directed movements is caused by defective recruitment of the myosin motor, Myo2. Intriguingly, intact mitochondria that are present in the same cell continue to move into the bud, establishing that quality control occurs directly at the level of the organelle in the mother. The selection of healthy organelles for inheritance no longer works in the absence of the mitochondrial Myo2 adapter protein Mmr1. Together, our data suggest a mechanism in which the combination of blocked fusion and loss of motor protein ensures that damaged mitochondria are retained in the mother cell to ensure rejuvenation of the bud.

Abstract Background Fracture risk assessment is still far from perfect within the geriatric population. The overall aim of this study is to better identify older women at risk for fractures, using a quantitative measure of frailty in conjunction with the web-based Fracture Risk Assessment Tool (FRAX®). Methods This study was performed in the Osteoporosis Risk Assessment (OPRA) cohort of n = 1023, 75-year-old women followed for 10-years. A frailty index (FI) of ‘deficits in health’ was created, and FRAX 10-year probability for major osteoporotic and hip fractures was calculated and bone mineral density measured. Incident fractures were continuously registered for 10-years. Receiver Operating Characteristic (ROC) curves were used to compare FI, FRAX and the combination FI + FRAX as instruments for risk prediction. Discriminative ability was estimated by comparing Area Under the Curve (AUC). In addition, using guidelines from the Swedish Osteoporosis Foundation, a category of low risk women who would not have been recommended for pharmacological treatment (non-treatment group) was identified, categorized by frailty status and for relative risk analysis, hazard ratios (HR) and 95% confidence intervals were calculated using Cox proportional hazard regressions. Results For hip fracture, FRAX and frailty performed almost equally (HIP AUC 10y: 0.566 vs. 0.567, p = 0.015 and p = 0.013). Next, FI was used in conjunction with FRAX; proving marginally better than either score alone (AUC 10y: 0.584, p = 0.002). Comparable results were observed for osteoporotic fracture. In the non-treatment group (564 women), being frail was associated with higher 10y hip fracture risk (HR 2.01 (1.13–3.57)), although failing to reach statistical significance for osteoporotic fracture (HR 1.40 (0.97–2.01). The utility of measuring frailty was also demonstrated when using T-score as an index of bone density to define fracture risk. Among n = 678 non-osteoporotic women, frailty added to the 10-year fracture risk (Hip; HR 2.22 (1.35–3.71); Osteoporotic fracture; HR 1.57 (1.15–2.14)). Conclusions While the addition of frailty to FRAX marginally improved fracture prediction, applying a frailty measurement to a group of ‘low risk’ women, identified a set of individuals with high actual hip fracture risk that would not be prioritized for pharmacological treatment. Further cost-benefit analysis studies are needed to formally test potential benefit.

NTHL1 tumor syndrome is an autosomal recessive rare disease caused by biallelic inactivating variants in the NTHL1 gene and which presents a broad tumor spectrum. To contribute to the characterization of the phenotype of this syndrome, we studied 467 index patients by KASP assay or next-generation sequencing, including 228 patients with colorectal polyposis and 239 patients with familial/personal history of multiple tumors (excluding multiple breast/ovarian/polyposis). Three NTHL1 tumor syndrome families were identified in the group of patients with polyposis and none in patients with familial/personal history of multiple tumors. Altogether, we identified nine affected patients with polyposis (two of them diagnosed after initiating colorectal cancer surveillance) with biallelic pathogenic or likely pathogenic NTHL1 variants, as well as two index patients with one pathogenic or likely pathogenic NTHL1 variant in concomitance with a missense variant of uncertain significance. Here we identified a novel inframe deletion classified as likely pathogenic using the ACMG criteria, supported also by tumor mutational signature analysis. Our findings indicate that the NTHL1 tumor syndrome is a multi-tumor syndrome strongly associated with polyposis and not with multiple tumors without polyposis.

Background: The healing of a bone injury is a highly complex process involving a multitude of different tissue and cell types, including immune cells, which play a major role in the initiation and progression of bone regeneration. Methods: We histologically analyzed the spatio-temporal occurrence of cells of the innate immune system (macrophages), the adaptive immune system (B and T lymphocytes), and bone cells (osteoblasts and osteoclasts) in the fracture area of a femoral osteotomy over the healing time. This study was performed in a bone osteotomy gap mouse model. We also investigated two key challenges of successful bone regeneration: hypoxia and revascularization. Results: Macrophages were present in and around the fracture gap throughout the entire healing period. The switch from initially pro-inflammatory M1 macrophages to the anti-inflammatory M2 phenotype coincided with the revascularization as well as the appearance of osteoblasts in the fracture area. This indicates that M2 macrophages are necessary for the restoration of vessels and that they also play an orchestrating role in osteoblastogenesis during bone healing. The presence of adaptive immune cells throughout the healing process emphasizes their essential role for regenerative processes that exceeds a mere pathogen defense. B and T cells co-localize consistently with bone cells throughout the healing process, consolidating their crucial role in guiding bone formation. These histological data provide, for the first time, comprehensive information about the complex interrelationships of the cellular network during the entire bone healing process in one standardized set up. With this, an overall picture of the spatio-temporal interplay of cellular key players in a bone healing scenario has been created. Conclusions: A spatio-temporal distribution of immune cells, bone cells, and factors driving bone healing at time points that are decisive for this process—especially during the initial steps of inflammation and revascularization, as well as the soft and hard callus phases—has been visualized. The results show that the bone healing cascade does not consist of five distinct, consecutive phases but is a rather complex interrelated and continuous process of events, especially at the onset of healing.

An ideal fixation system for guided bone (GBR) regeneration in oral surgery must fulfil several criteria that includes the provision of adequate mechanical fixation, complete resorption when no longer needed, complete replacement by bone, as well as be biocompatible and have a good clinical manageability. For the first time, a biodegradable magnesium fixation screw made of the magnesium alloy WZM211 with a MgF2 coating has been designed and tested to fulfill these criteria. Adequate mechanical fixation was shown for the magnesium fixation screw in several benchtop tests that directly compared the magnesium fixation screw with an equivalent polymeric resorbable device. Results demonstrated slightly superior mechanical properties of the magnesium device in comparison to the polymeric device even after 4 weeks of degradation. Biocompatibility of the magnesium fixation screw was demonstrated in several in vitro and in vivo tests. Degradation of the magnesium screw was investigated in in vitro and in vivo tests, where it was found that the screw is resorbed slowly and completely after 52 weeks, providing adequate fixation in the early critical healing phase. Overall, the magnesium fixation screw demonstrates all of the key properties required for an ideal fixation screw of membranes used in guided bone regeneration (GBR) surgeries.

Most of the 2,100 CFTR gene variants reported to date are still unknown in terms of their disease liability in Cystic Fibrosis (CF) and their molecular and cellular mechanism that leads to CFTR dysfunction. Since some rare variants may respond to currently approved modulators, characterizing their defect and response to these drugs is essential for effective treatment of people with CF (pwCF) not eligible for the current treatment. Here, we assessed how the rare variant, p.Arg334Trp, impacts on CFTR traffic and function and its response to existing CFTR modulators. To this end, we performed the forskolin-induced swelling (FIS) assay on intestinal organoids from 10 pwCF bearing the p.Arg334Trp variant in one or both alleles of the CFTR gene. In parallel, a novel p.Arg334Trp-CFTR expressing CFBE cell line was generated to characterize the variant individually. Results show that p.Arg334Trp-CFTR does not significantly affect the plasma membrane traffic of CFTR and evidences residual CFTR function. This CFTR variant is rescued by currently available CFTR modulators independently of the variant in the second allele. The study, predicting clinical benefit for CFTR modulators in pwCF with at least one p.Arg334Trp variant, demonstrates the high potential of personalized medicine through theranostics to extend the label of approved drugs for pwCF carrying rare CFTR variants. We recommend that this personalized approach should be considered for drug reimbursement policies by health insurance systems/national health services.

Background & Aims: Chronic HCV infection causes cellular stress, fibrosis and predisposes to hepatocarcinogenesis. Mitochondria play key roles in orchestrating stress responses by regulating bioenergetics, inflammation and apoptosis. To better understand the role of mitochondria in the viral life cycle and disease progression of chronic hepatitis C, we studied morphological and functional mitochondrial alterations induced by HCV using productively infected hepatoma cells and patient livers. Methods: Biochemical and imaging assays were used to assess localization of cellular and viral proteins and mitochondrial functions in cell cultures and liver biopsies. Cyclophilin D (CypD) knockout was performed using CRISPR/Cas9 technology. Viral replication was quantified by quantitative reverse-transcription PCR and western blotting. Results: Several HCV proteins were found to associate with mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs), the points of contact between the ER and mitochondria. Downregulation of CypD, which is known to disrupt MAM integrity, reduced viral replication, suggesting that MAMs play an important role in the viral life cycle. This process was rescued by ectopic CypD expression. Furthermore, HCV proteins were found to associate with voltage dependent anion channel 1 (VDAC1) at MAMs and to reduce VDAC1 protein levels at MAMs in vitro and in patient biopsies. This association did not affect MAM-associated functions in glucose homeostasis and Ca2+ signaling. Conclusions: HCV proteins associate specifically with MAMs and MAMs play an important role in viral replication. The association between viral proteins and MAMs did not impact Ca2+ signaling between the ER and mitochondria or glucose homeostasis. Whether additional functions of MAMs and/or VDAC are impacted by HCV and contribute to the associated pathology remains to be assessed. Impact and implications: Hepatitis C virus infects the liver, where it causes inflammation, cell damage and increases the long-term risk of liver cancer. We show that several HCV proteins interact with mitochondria in liver cells and alter the composition of mitochondrial subdomains. Importantly, HCV requires the architecture of these mitochondrial subdomains to remain intact for efficient viral replication.

INTRODUCTION: Normal pressure hydrocephalus (NPH) patients undergoing cortical shunting frequently show early Alzheimer's disease (AD) pathology on cortical biopsy, which is predictive of progression to clinical AD. The objective of this study was to use samples from this cohort to identify cerebrospinal fluid (CSF) biomarkers for AD‐related central nervous system (CNS) pathophysiologic changes using tissue and fluids with early pathology, free of post mortem artifact. METHODS: We analyzed Simoa, proteomic, and metabolomic CSF data from 81 patients with previously documented pathologic and transcriptomic changes. RESULTS: AD pathology on biopsy correlates with CSF β‐amyloid‐42/40, neurofilament light chain (NfL), and phospho‐tau‐181(p‐tau181)/β‐amyloid‐42, while several gene expression modules correlate with NfL. Proteomic analysis highlights seven core proteins that correlate with pathology and gene expression changes on biopsy, and metabolomic analysis of CSF identifies disease‐relevant groups that correlate with biopsy data. DISCUSSION: As additional biomarkers are added to AD diagnostic panels, our work provides insight into the CNS pathophysiology these markers are tracking. Highlights: AD CSF biomarkers correlate with CNS pathology and transcriptomic changes.Seven proteins correlate with CNS pathology and gene expression changes.Inflammatory and neuronal gene expression changes correlate with YKL‐40 and NPTXR, respectively.CSF metabolomic analysis identifies pathways that correlate with biopsy data.Fatty acid metabolic pathways correlate with β‐amyloid pathology. [ABSTRACT FROM AUTHOR]

To investigate the use of kinetic parameters derived from direct Patlak reconstructions of [68Ga]Ga-PSMA-11 positron emission tomography/computed tomography (PET/CT) to predict the histological grade of malignancy of the primary tumor of patients with prostate cancer (PCa). Thirteen patients (mean age 66 ± 10 years) with a primary, therapy-naïve PCa (median PSA 9.3 [range: 6.3–130 µg/L]) prior radical prostatectomy, were recruited in this exploratory prospective study. A dynamic whole-body [68Ga]Ga-PSMA-11 PET/CT scan was performed for all patients. Measured quantification parameters included Patlak slope (Ki: absolute rate of tracer consumption) and Patlak intercept (Vb: degree of tracer perfusion in the tumor). Additionally, the mean and maximum standardized uptake values (SUVmean and SUVmax) of the tumor were determined from a static PET 60 min post tracer injection. In every patient, initial PSA (iPSA) values that were also the PSA level at the time of the examination and final histology results with Gleason score (GS) grading were correlated with the quantitative readouts. Collectively, 20 individual malignant prostate lesions were ascertained and histologically graded for GS with ISUP classification. Six lesions were classified as ISUP 5, two as ISUP 4, eight as ISUP 3, and four as ISUP 2. In both static and dynamic PET/CT imaging, the prostate lesions could be visually distinguished from the background. The average values of the SUVmean, slope, and intercept of the background were 2.4 (±0.4), 0.015 1/min (±0.006), and 52% (±12), respectively. These were significantly lower than the corresponding parameters extracted from the prostate lesions (all p < 0.01). No significant differences were found between these values and the various GS and ISUP (all p > 0.05). Spearman correlation coefficient analysis demonstrated a strong correlation between static and dynamic PET/CT parameters (all r ≥ 0.70, p < 0.01). Both GS and ISUP grading revealed only weak correlations with the mean and maximum SUV and tumor-to-background ratio derived from static images and dynamic Patlak slope. The iPSA demonstrated no significant correlation with GS and ISUP grading or with dynamic and static PET parameter values. In this cohort of mainly high-risk PCa, no significant correlation between [68Ga]Ga-PSMA-11 perfusion and consumption and the aggressiveness of the primary tumor was observed. This suggests that the association between SUV values and GS may be more distinctive when distinguishing clinically relevant from clinically non-relevant PCa.

ABSTRACT Viral infections attract more and more attention, especially after the emergence of novel zoonotic coronaviruses and the monkeypox virus over the last 2 decades. Research on viruses is based to a great extent on mammalian cell lines that are permissive to the respective viruses. These cell lines are usually cultivated according to the protocols established in the 1950s to 1970s, although it is clear that classical media have a significant imprint on cell growth, phenotype, and especially metabolism. So, recently in the field of biochemistry and metabolomics novel culture media have been developed that resemble human blood plasma. As perturbations in metabolic and redox pathways during infection are considered significant factors of viral pathogenesis, these novel medium formulations should be adapted by the virology field. So far, there are only scarce data available on viral propagation efficiencies in cells cultivated in plasma-like media. But several groups have presented convincing data on the use of such media for cultivation of uninfected cells. The aim of the present review is to summarize the current state of research in the field of plasma-resembling culture media and to point out the influence of media on various cellular processes in uninfected cells that may play important roles in viral replication and pathogenesis in order to sensitize virology research to the use of such media.

In this paper, particular key aspects of the philosophies of Plotinus and Wang Yangming have been analysed comparatively on the basis of important passages of their works. The method used for this investigation can be defined as that of transversal comparative induction, in which the focus is more on working out the details of affinities and similarities. As this means a first step in an encompassing systematic context, differences will be introduced more briefly. The present investigation aims to provide a foundation for a more differentiating and therefore complementing second part, which will consider other contents and topics in both philosophies. The present analysis is performed in three systematic steps and with regard to three basic philosophical ideas: (1) the idea that human consciousness is a central medium in the universal process and interrelatedness of (biological) life as a whole; (2) the idea that the self-unfoldment of reality represents a meta-cognitive process beyond the limits of subjectivity and finite consciousness; and (3) the idea that it is our major task to perfect and know ourselves by means of a “return” to the highest underlying foundation of this universal process. In their own ways, Plotinus and Wang Yangming both show that by enfolding human reflexivity toward the ineffable source of all reality in thought, feeling, human activity, and natural processes, namely by actively pursuing the path of moral and intellective perfection, we become fulfilled mediators of a universal process and of that which all of it represents.

Vocational interest inventories play an important role in supporting adolescents and young adults in their vocational choice. However, existing verbal and pictorial questionnaires have limitations regarding the complexity, abstraction level, and ambiguity of the item material. The presented research attempts to overcome these limitations by developing a new pictorial questionnaire. Study 1 describes the construction process of the Nonverbal Vocational Interest Scale (NVIS) and its psychometric properties, evaluation, and construct validation. Data from N = 363 adolescents and young adults in lower secondary school and vocational training centres were considered. Study 2 was conducted to confirm convergent and discriminant validity. N = 237 adolescents and young adults completed the revised form of the NVIS and the Photo-Interest-Inventory (F-I-T). The results confirm that the NVIS is a reliable and valid computer-based instrument for assessing vocational interests. Limitations and implications for further research and use in vocational training and counselling settings are discussed.

Specific transcriptional changes in microglia associated with Alzheimer’s disease have been reported. Here, the authors show that transcriptional analysis of human hydrocephalus biopsies identifies changes in immune response genes associated with early AD pathology, including cognitive decline.

This article provides a transcultural, “transversal” investigation. It starts from the philosophical problem of knowing non-knowing. In chapters 1 and 2, the first expressions of this problem by Confucius and Socrates are considered. Against this background, new transcultural working concepts are developed. A new key term to be established here is that of an “implicate logic”. It refers to the reflection of unity of unity and difference and therefore to the very condition of the possibility of (differentiating) thinking as such. In chapters 3 and 4, this train of thought is further developed under the influence of Nicolaus Cusanus, by reflecting on the first chapter of the Daodejing, and in view of important remarks by Niklas Luhmann. In chapter 5, the outcome is related to the idea of transversal reason in the philosophy of Wolfgang Welsch. As the most basic principle of (self-referential) thinking, implicate logic is to be discerned from Aristotelian (or similar traditions of) logic and Hegelian dialectics—albeit both are being tied to the former’s principle in one way or the other. In the end, an introductory outlook of a comprehensive work by the present author provides the starting point to validate the logical foundations of knowing non-knowing as a methodological foundation to further develop the fields of transcultural-comparative, trans-comparative, and global philosophy.

Abstract Pretermbirth (PTB) is a major obstetric problem associated with high rates of neonatal morbidity and mortality. The prevalence of PTB has not changed in the last decade; thus, the establishment of a screening test and effective treatment are warranted. Transvaginal ultrasoundmeasurement of the cervical length (TUCL) has been proposed as an effective method to screen pregnant women at a higher risk of experiencing PTB. Objective To evaluate the applicability and usefulness of second-trimester TUCL to predict PTB in a cohort of Portuguese pregnant women. Methods Retrospective cross-sectional cohort study including all singleton pregnant women who performed their second-trimester ultrasound (between weeks 18 and 22þ6 days) from January 2013 to October 2017 at Centro Hospitalar Universitário São João. Results Our cohort included 4,481 women. The prevalence of spontaneous PTB was of 4.0%, with 0.7% occurring before the 34th week of gestation. The mean TUCL was of 33.8mm,and percentiles 3, 5 and 10 corresponded toTUCLs of 25.0mm, 27.0mmand 29.0mmrespectively. The multiple logistic regression analysis, including maternal age, previous PTB and cervical surgery showed a significant negative association between TUCL and PTB, with an odds ratio (OR) of 0.92 (95% confidence interval [95%CI]: 0.90-0.95; p

BackgroundEndometrial carcinoma (EC) is the most common gynecologic malignancy in developed countries and the fourth most frequent in women worldwide. The cornerstone of treatment for EC is surgery. Clinicopathological features are currently used to help determine the individual risk of recurrence and the need for adjuvant treatment after surgery. Nonetheless, there is significant interobserver variability in assigning histologic subtype when using a morphological classification, revealing the need for a more unified approach. The Cancer Genome Atlas (TCGA) project identified 4 distinct prognostic EC subtypes based on genomic abnormalities. Surrogate assays including 3 immunohistochemical markers (p53, MSH6, and PMS2) and 1 molecular test (mutation analysis of the exonuclease domain of DNA polymerase epsilon; POLE) allowed the development and validation of a simplified molecular classifier that correlates with the TCGA classification, has prognostic value, and can easily be used in clinical practice. This molecular classification categorizes EC in 4 subtypes: POLE mutated, mismatch repair–deficient, p53 abnormal, and no specific molecular profile. Applying this classification in clinical practice will help tailor adjuvant treatment decisions. ObjectiveThe aim of this study is to retrospectively apply this novel molecular classification to a cohort of patients with EC treated in a comprehensive cancer center, to assess its applicability in clinical practice, to evaluate clinical outcomes by molecular subtypes, and to assess its prognostic value. MethodsIn this retrospective cohort study, patients with primary EC diagnosed during and after 2013 and treated or followed at our institution, after definite surgery, will be included. Demographic and clinicopathological data will be obtained from electronic health records and from pathology reports. Laboratory methods will include immunohistochemical study of p53 and mismatch repair proteins, as well as POLE mutational analysis by genetic sequencing. The primary end point is recurrence-free survival and secondary end points are disease-specific survival and overall survival. A descriptive analysis of variables will be carried out. Survival analysis will be performed using the Kaplan-Meier method and the groups will be compared using the log-rank test. ResultsThis protocol was reviewed and approved by the Instituto Português de Oncologia do Porto, Portugal, ethics committee in October 2021; patient selection from our cancer registry began the same month. A total of 160 patients will be included. This work will present real-life results that will allow a better understanding of the Portuguese EC population and the distribution of the molecular subgroups throughout. We will use these results to understand the prognostic value of this classification in our population and its role in adjuvant therapy decisions. This study is anticipated to conclude in December 2022. ConclusionsThis study will provide important information regarding these women’s outcomes according to this new molecular classification and will support its use when discussing a patient’s need for adjuvant treatment. International Registered Report Identifier (IRRID)PRR1-10.2196/34461

Abstract This study aimed to clarify the role of glypican-1 and PECAM-1 in shear-induced nitric oxide production in endothelial cells. Atomic force microscopy pulling was used to apply force to glypican-1 and PECAM-1 on the surface of human umbilical vein endothelial cells and nitric oxide was measured using a fluorescent reporter dye. Glypican-1 pulling for 30 min stimulated nitric oxide production while PECAM-1 pulling did not. However, PECAM-1 downstream activation was necessary for the glypican-1 force-induced response. Glypican-1 knockout mice exhibited impaired flow-induced phosphorylation of eNOS without changes to PECAM-1 expression. A cooperation mechanism for the mechanotransduction of fluid shear stress to nitric oxide production was elucidated in which glypican-1 senses flow and phosphorylates PECAM-1 leading to endothelial nitric oxide synthase phosphorylation and nitric oxide production.

Hepatitis delta virus (HDV) is a viroid-like satellite that may co-infect individuals together with hepatitis B virus (HBV), as well as cause superinfection by infecting patients with chronic hepatitis B (CHB). Being a defective virus, HDV requires HBV structural proteins for virion production. Although the virus encodes just two forms of its single antigen, it enhances the progression of liver disease to cirrhosis in CHB patients and increases the incidence of hepatocellular carcinoma. HDV pathogenesis so far has been attributed to virus-induced humoral and cellular immune responses, while other factors have been neglected. Here, we evaluated the impact of the virus on the redox status of hepatocytes, as oxidative stress is believed to contribute to the pathogenesis of various viruses, including HBV and hepatitis C virus (HCV). We show that the overexpression of large HDV antigen (L-HDAg) or autonomous replication of the viral genome in cells leads to increased production of reactive oxygen species (ROS). It also leads to the upregulated expression of NADPH oxidases 1 and 4, cytochrome P450 2E1, and ER oxidoreductin 1α, which have previously been shown to mediate oxidative stress induced by HCV. Both HDV antigens also activated the Nrf2/ARE pathway, which controls the expression of a spectrum of antioxidant enzymes. Finally, HDV and its large antigen also induced endoplasmic reticulum (ER) stress and the concomitant unfolded protein response (UPR). In conclusion, HDV may enhance oxidative and ER stress induced by HBV, thus aggravating HBV-associated pathologies, including inflammation, liver fibrosis, and the development of cirrhosis and hepatocellular carcinoma.

Reactive oxygen species (ROS) play a major role in the regulation of various processes in the cell. The increase in their production is a factor contributing to the development of numerous pathologies, including inflammation, fibrosis, and cancer. Accordingly, the study of ROS production and neutralization, as well as redox-dependent processes and the post-translational modifications of proteins, is warranted. Here, we present a transcriptomic analysis of the gene expression of various redox systems and related metabolic processes, such as polyamine and proline metabolism and the urea cycle in Huh7.5 hepatoma cells and the HepaRG liver progenitor cell line, that are widely used in hepatitis research. In addition, changes in response to the activation of polyamine catabolism that contribute to oxidative stress were studied. In particular, differences in the gene expression of various ROS-producing and ROS-neutralizing proteins, the enzymes of polyamine metabolisms and proline and urea cycles, as well as calcium ion transporters between cell lines, are shown. The data obtained are important for understanding the redox biology of viral hepatitis and elucidating the influence of the laboratory models used.

Low-grade serous ovarian cancer (LGSOC) is now considered a different entity from high-grade serous ovarian cancer. The chemoresistance inherent to this type of ovarian cancer narrows the therapeutic options, especially in the recurrent setting. It is thought that the mitogen-activated protein kinase (MAPK) pathway plays a significant role in the pathogenesis of these tumours, and about 2 to 20% of LGSOC harbour a BRAF mutation. Here we present a case report of two patients with a BRAF V600E mutation that achieved sustained clinical responses with combination treatment with dabrafenib (BRAF inhibitor) and trametinib (MEK inhibitor).

Introduction: Accumulation of epicardial adipose tissue (EAT) is associated with coronary artery disease (CAD) and increased risk of coronary events in asymptomatic subjects and low-risk patients, suggesting that EAT promotes atherosclerosis in its early stage. Recent studies have shown that the presence of CAD affects the properties of adjacent EAT, leading to dynamic changes in the molecular players involved in the interplay between EAT and the coronary arteries over the history of the disease. The role of EAT in late-stage CAD has not been investigated. Objectives: In a comparative analysis with mediastinal and subcutaneous adipose tissue, we aim to investigate whether the volume of EAT assessed by computed tomography and its proteome assessed by SWATH-MS mass spectrometry are associated with late stages of CAD in an elderly cohort of severe aortic stenosis patients. Methods: The EPICHEART study (NCT03280433) is a prospective study enrolling patients with severe degenerative aortic stenosis referred for elective aortic valve replacement, whose protocol includes preoperative clinical, nutritional, echocardiographic, cardiac computed tomography and invasive coronary angiographic assessments. During cardiac surgery, samples of EAT and mediastinal and subcutaneous thoracic adipose tissue are collected for proteomics analysis by SWATH-MS. In addition, pericardial fluid and peripheral and coronary sinus blood samples are collected to identify circulating and local adipose tissue-derived biomarkers of CAD. Conclusion: We designed a translational study to explore the association of EAT quantity and quality with advanced CAD. We expect to identify new biochemical factors and biomarkers in the crosstalk between EAT and the coronary arteries that are involved in the pathogenesis of late coronary atherosclerosis, especially coronary calcification, which might be translated into new therapeutic targets and imaging tools by biomedical engineering. Resumo: Introdução: Acumulação de tecido adiposo epicárdico (TAE) tem sido associado a doença coronária aterosclerótica (DC) e aumento do risco de eventos coronários em indivíduos assintomáticos e doentes de baixo risco, sugerindo que o TAE pode promover fases precoces da DC. Estudo recentes mostraram que a presença de DC afeta as características do TAE adjacente levando a modificações dinâmicas nos mediadores envolvidos na comunicação entre o TAE e as artérias coronárias ao longo da história da DC. O papel doTAE nas fases avançadas da aterosclerose coronária não foi investigado. Objetivos: Através de análise comparativa com o tecido adiposo mediastínico e subcutâneo, pretendemos investigar se o volume do TAE, avaliado por tomografia computadorizada (TC), e o seu proteoma, avaliado por espectrometria de massa técnica de SWATH, estão associados a estadios avançados da DC numa coorte de estenose aórtica grave. Métodos: O estudo EPICHEART (NCT03280433) é um estudo prospetivo que inclui doentes com estenose aórtica grave referenciados para substituição eletiva da válvula aórtica, cujo protocolo envolve avaliação pré-operatória clínica, nutricional, ecocardiográfica, por TC e angiografia coronária invasiva. Durante a cirurgia cardíaca, colhemos amostras de tecido adiposo epicárdico, mediastínico e subcutâneo para análise do seu proteoma por espectrometria de massa técnica de SWATH. Adicionalmente, colhemos líquido pericárdico, sangue venoso periférico e do seio coronário para investigar mediadores de DC derivados do TAE na circulação sistémica e local. Conclusão: Desenhámos um estudo de translação para explorar a associação da quantidade e qualidade do TAE com a DC tardia. Esperamos identificar mediadores da comunicação recíproca entre o TAE e as artérias coronárias que estão envolvidos na patogénese das fases avançadas da DC, especialmente, calcificação coronária, os quais podem servir como novos alvos terapêuticos e soluções de engenharia biomédica para visualização da DC.

This essay delves into the diversity of animal stories in human meaning ecologies and argues that the ‘lessons’ to be derived from these stories revolve around the meaning and effect of various forms of ambiguity. Following the route of a selection of mostly Irish canonical texts, from Swift’s Gulliver’s Travels to Seamus Heaney’s Death of a Naturalist, it formulates seven lessons for reading and teaching animal fictions in a multispecies world. It argues that we must cultivate a sense of ‘ciferal’ reading that does not resolve but thrives productively on the tensions and ambiguities of human-animal relations that literary fiction excels in putting into words.

We present a new high-precision, JWST-based, strong-lensing model for the galaxy cluster Abell 2744 at z = 0.3072. By combining the deep, high-resolution JWST imaging from the Grism Lens Amplified Survey from Space–JWST and Ultradeep NIRSpec and NIRCam Observations before the Epoch of Reionization programs and a Director’s Discretionary Time program, with newly obtained Very Large Telescope/Multi Unit Spectroscopic Explorer (MUSE) data, we identify 32 multiple images from 11 background sources lensed by two external subclusters at distances of ∼160″ from the main cluster. The new MUSE observations enable the first spectroscopic confirmation of a multiple-image system in the external clumps. Moreover, the reanalysis of the spectrophotometric archival and JWST data yields 27 additional multiple images in the main cluster. The new lens model is constrained by 149 multiple images (∼66% more than in our previous model) covering an extended redshift range between 1.03 and 9.76. The subhalo mass component of the cluster includes 177 member galaxies down to m _F160W = 21, of which 163 are spectroscopically confirmed. Internal velocity dispersions are measured for 85 members. The new lens model is characterized by a remarkably low scatter between the predicted and observed positions of the multiple images (0.″43). This precision is unprecedented given the large multiple-image sample, the complexity of the cluster mass distribution, and the large modeled area. The improved precision and resolution of the cluster total mass distribution provides a robust magnification map over a ∼30 arcmin ^2 area, which is critical for inferring the intrinsic physical properties of the highly magnified, high- z sources. The lens model and the new MUSE redshift catalog are released with this publication.

Introduction to OLH Special Collection 'Reading in Ruins: Exploring Posthumanist Narrative Studies'