Novel Systemic Treatments in High Grade Ovarian Cancer

Most patients with ovarian cancer present at an advanced stage and are never cured. To improve outcomes a variety of novel systemic strategies are being developed. Traditional cytotoxic chemotherapy is being optimised, anti-angiogenic strategies are already in the clinic and several PARP inhibitors have gained regulatory approval. In addition, immunotherapy is showing promise and novel targeted strategies including against folate receptor alpha are also generating excitement. As our therapeutic choice increases, a challenge will be how to best utilize the options available. Here we discuss recently established and other emerging therapies with a focus on key concepts rather than detailed synopses of trial designs and outcomes

Breast Cancer in the Setting of HIV

Oncogenesis in immunocompromised patients occurs due to a number of factors including reduced immune surveillance or other viral pathogens. Breast cancer, unlike other non-AIDS-defining cancers, does not appear associated and has rarely been reported. We describe a case with evidence of immune reactivity around the tumor, but not in the tumor itself

Effectiveness and Acceptability of e- and m-Health Interventions to Promote Physical Activity and Prevent Falls in Nursing Homes—A Systematic Review

Age-related decreases in physical activity (PA) and a decline in physical functioning lead to increased fall risk. As falls are a major cause of accidental deaths and hospitalization in older adults, PA promotion and fall prevention are important measures, especially in nursing homes (NH). With advances in information and communication technology, e- and m-health solutions have been developed to positively influence various health-related factors. To date, only little research exists on the implementation of these technologies to promote health in NH. Therefore, the objective of this systematic review was to provide an overview of the effectiveness, acceptability, and feasibility of e- and m-health interventions aimed at promoting PA and preventing falls in NH. Additionally, the effectiveness of such interventions regarding the secondary outcomes physical function, cognitive function, neuropsychiatric symptoms, and psychosocial status was examined. A systematic literature search was performed in five databases and studies published until 15 November 2021, were considered for inclusion. All studies that examined the effectiveness and/or the acceptability and feasibility of e- or m-health interventions in promoting PA and preventing falls in NH, without restriction on language or date of publication, were included in the final synthesis. Of the 1,358 records retrieved, 28 studies were included in this systematic review. Twenty-four studies contained digital exergaming as an intervention or as a part of the intervention, the four additional studies on e-health interventions only examined a small number of outcomes. No m-health intervention study was identified. Data synthesis indicates that exergaming may be effective in reducing the number of falls and fall risk in NH residents. Several significant improvements were also reported regarding secondary outcomes albeit not consistent across studies. No conclusion can be drawn about the effects of exergaming and other e-health interventions on PA, as data is scarce. E-health interventions were mostly reported as feasible and well accepted by NH residents. However, these findings may not be applicable to NH residents with advanced physical and/or cognitive impairments, since they were excluded in many studies. Therefore, more research examining other digital solutions besides exergaming to promote PA in this specific population is critical. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/, identifier CRD4202128948

TP53 regulates miRNA association with AGO2 to remodel the miRNA-mRNA interaction network

DNA damage activates TP53-regulated surveillance mechanisms that are crucial in suppressing tumorigenesis. TP53 orchestrates these responses directly by transcriptionally modulating genes, including microRNAs (miRNAs), and by regulating miRNA biogenesis through interacting with the DROSHA complex. However, whether the association between miRNAs and AGO2 is regulated following DNA damage is not yet known. Here, we show that, following DNA damage, TP53 interacts with AGO2 to induce or reduce AGO2's association of a subset of miRNAs, including multiple let-7 family members. Furthermore, we show that specific mutations in TP53 decrease rather than increase the association of let-7 family miRNAs, reducing their activity without preventing TP53 from interacting with AGO2. This is consistent with the oncogenic properties of these mutants. Using AGO2 RIP-seq and PAR-CLIP-seq, we show that the DNA damage–induced increase in binding of let-7 family members to the RISC complex is functional. We unambiguously determine the global miRNA–mRNA interaction networks involved in the DNA damage response, validating them through the identification of miRNA-target chimeras formed by endogenous ligation reactions. We find that the target complementary region of the let-7 seed tends to have highly fixed positions and more variable ones. Additionally, we observe that miRNAs, whose cellular abundance or differential association with AGO2 is regulated by TP53, are involved in an intricate network of regulatory feedback and feedforward circuits. TP53-mediated regulation of AGO2–miRNA interaction represents a new mechanism of miRNA regulation in carcinogenesis

Sustained expression of miR-26a promotes chromosomal instability and tumorigenesis through regulation of CHFR

MicroRNA 26a (miR-26a) reduces cell viability in several cancers, indicating that miR-26a could be used as a therapeutic option in patients. We demonstrate that miR-26a not only inhibits G1-S cell cycle transition and promotes apoptosis, as previously described, but also regulates multiple cell cycle checkpoints. We show that sustained miR-26a over-expression in both breast cancer (BC) cell lines and mouse embryonic fibroblasts (MEFs) induces oversized cells containing either a single-large nucleus or two nuclei, indicating defects in mitosis and cytokinesis. Additionally, we demonstrate that miR-26a induces aneuploidy and centrosome defects and enhances tumorigenesis. Mechanistically, it acts by targeting G1-S transition genes as well as genes involved in mitosis and cytokinesis such as CHFR, LARP1 and YWHAE. Importantly, we show that only the re-expression of CHFR in miR-26a over-expressing cells partially rescues normal mitosis and impairs the tumorigenesis exerted by miR-26a, indicating that CHFR represents an important miR-26a target in the regulation of such phenotypes. We propose that miR-26a delivery might not be a viable therapeutic strategy due to the potential deleterious oncogenic activity of this miRNA

The germline of the malaria mosquito produces abundant miRNAs, endo-siRNAs, piRNAs and 29-nt small RNA

BACKGROUND Small RNAs include different classes essential for endogenous gene regulation and cellular defence against genomic parasites. However, a comprehensive analysis of the small RNA pathways in the germline of the mosquito Anopheles gambiae has never been performed despite their potential relevance to reproductive capacity in this malaria vector. RESULTS We performed small RNA deep sequencing during larval and adult gonadogenesis and find that they predominantly express four classes of regulatory small RNAs. We identified 45 novel miRNA precursors some of which were sex-biased and gonad-enriched , nearly doubling the number of previously known miRNA loci. We also determine multiple genomic clusters of 24-30 nt Piwi-interacting RNAs (piRNAs) that map to transposable elements (TEs) and 3'UTR of protein coding genes. Unusually, many TEs and the 3'UTR of some endogenous genes produce an abundant peak of 29-nt small RNAs with piRNA-like characteristics. Moreover, both sense and antisense piRNAs from TEs in both Anopheles gambiae and Drosophila melanogaster reveal novel features of piRNA sequence bias. We also discovered endogenous small interfering RNAs (endo-siRNAs) that map to overlapping transcripts and TEs. CONCLUSIONS This is the first description of the germline miRNome in a mosquito species and should prove a valuable resource for understanding gene regulation that underlies gametogenesis and reproductive capacity. We also provide the first evidence of a piRNA pathway that is active against transposons in the germline and our findings suggest novel piRNA sequence bias. The contribution of small RNA pathways to germline TE regulation and genome defence in general is an important finding for approaches aimed at manipulating mosquito populations through the use of selfish genetic elements

Digitale Bewegungsförderung und Sturzprävention in Pflegeeinrichtungen – der Status-Quo von Technikaffinität und der Bereitschaft zur Nutzung digitaler Lösungen bei Pflegepersonal [Promoting physical activity and preventing falls with digital tools in care facilities - the status quo of affinity for technology and willingness to use digital solutions among nursing home employees]

Hintergrund: Die Bedeutung der Digitalisierung im Gesundheitswesen wächst seit Jahren. Diese Studie untersucht das Ausmaß der Nutzung und Implementierung digitaler Lösungen im Bereich der Bewegungsförderung im Setting Pflege sowie die Technikaffinität und die Bereitschaft des Pflegepersonals zur Nutzung digitaler Lösungen. Ein weiterer Fokus liegt auf den Nutzungsbedingungen, die digitale Konzepte erfüllen sollten, sowie möglichen Risiken die bei der Nutzung derselbigen auftreten können. Methodik: Es wurde ein Onlinefragebogen mit quantitativen und qualitativen Fragestellungen zur Nutzungsbereitschaft und Voraussetzungen für digitale Lösungen entwickelt, unter Einbezug von zwei Fragebögen zur Technikaffinität (ATI und TA-EG). Die Pflegeeinrichtungen wurden deutschlandweit rekrutiert. Die Daten wurden qualitativ mit MAXQDA und quantitativ mit SPSS Version 27 analysiert. Ergebnisse: 200 Personen aus 15 Bundesländern nahmen an der Befragung teil. Eine flächendeckende Ausstattung mit digitalen Geräten und WLAN ist in Pflegeeinrichtungen noch nicht gegeben. Es zeigten sich signifikante Unterschiede in der Technikaffinität bezogen auf das Alter (t (198) = 3,705; p = 0,000), das Geschlecht (t (196) = -2,952; p = 0,004) und die berufliche Funktion (ATI: t (198) = 2,286; p = 0,023; TA-EG: t (198) = 2,126, p = 0,035). 47 % der Teilnehmenden haben keine Erfahrung mit digitalen Lösungen im Bereich Bewegungsförderung und Sturzprävention. Als Risiken wurden Stürze, falsche Übungsausführungen und Verringerung der sozialen Kontakte identifiziert. 65,4 % (n = 53) der Einrichtungsleitungen, und 54,6 % (n = 65) der Angestellten sind bereit eine digitale Lösung zu nutzen. Die Erwartungen beinhalteten eine gute Wirksamkeit, Individualisierungsmöglichkeiten, einfache Handhabung, sowie eine gute Alltagsintegration. Schlussfolgerung: Bei der Implementierung digitaler Lösungen muss die strukturelle, bislang wenig digitalisierte Situation von Pflegeeinrichtungen berücksichtigt werden. Die Ergebnisse zur Technikaffinität lassen darauf schließen, dass eine Bereitschaft zur Nutzung an sich vorhanden ist. Mögliche Risiken und bisherige Erfahrungen, sowie Erwartungen an digitale Lösungen müssen in die Entwicklung derselbigen einfließen, um eine langfristige Nutzung zu ermöglichen

Are nursing home employees ready for the technical evolution? German-wide survey on the status quo of affinity for technology and technology interaction

Background Technological devices can support nursing home employees; however, their perspective is not sufficiently studied. Our aims were thus to (a) examine affinity for technology and technology interaction and related sociodemographic confounders, as well as (b) detect possible requirements and boundary conditions relevant for the development and implementation of assistive technologies among nursing home employees. Methods We conducted an online survey between May and July of 2022 among 200 nursing home employees in Germany. The survey included two questionnaires, that is, Affinity for Technology Interaction (ATI) and Affinity for Technology—Electronic Devices (TA-EG; subscales TA-EG-Enthusiasm, TA-EG-Competence, TA-EG-Positive Consequences, and TA-EG-Negative Consequences), as well as sociodemographic variables, that is, age, gender, professional groups, education/graduation level. We carried out factorial variance and multiple regression analyses. Results There were differences between age groups in ATI (lower score with increasing age) and between gender, age, and professional group in TA-EG (lower score for females, participants with higher ages, and nursing home managers). Predictors of ATI were age and professional group, predictors of TA-EG, TA-EG-Enthusiasm, and TA-EG-Competence were gender, age, and professional group. Predictors of TA-EG-Positive Consequences were education and professional group. Conclusions We observed rather high affinity for technology and technology interaction values overall, and particularly for nursing home employees compared to managers. Significant predictors for technology affinity and interaction may have important implications, for example the perspectives of nursing home employees and managers should be considered separately in the technological design, development, and implementation process. Furthermore, an open dialogue between all stakeholders should be encouraged to increase the probability of actual technology use

miR-515-5p controls cancer cell migration through MARK4 regulation

Here, we show that miR-515-5p inhibits cancer cell migration and metastasis. RNA-seq analyses of both oestrogen receptor receptor-positive and receptor-negative breast cancer cells overexpressing miR-515-5p reveal down-regulation of NRAS, FZD4, CDC42BPA, PIK3C2B and MARK4 mRNAs. We demonstrate that miR-515-5p inhibits MARK4 directly 3' UTR interaction and that MARK4 knock-down mimics the effect of miR-515-5p on breast and lung cancer cell migration. MARK4 overexpression rescues the inhibitory effects of miR-515-5p, suggesting miR-515-5p mediates this process through MARK4 down-regulation. Furthermore, miR-515-5p expression is reduced in metastases compared to primary tumours derived from both in vivo xenografts and samples from patients with breast cancer. Conversely, miR-515-5p overexpression prevents tumour cell dissemination in a mouse metastatic model. Moreover, high miR-515-5p and low MARK4 expression correlate with increased breast and lung cancer patients' survival, respectively. Taken together, these data demonstrate the importance of miR-515-5p/MARK4 regulation in cell migration and metastasis across two common cancers

Glypican-1 is enriched in circulating-exosomes in pancreatic cancer and correlates with tumor burden

Background Glypican-1 (GPC1) is expressed in pancreatic ductal adenocarcinoma (PDAC) cells and adjacent stromal fibroblasts. Recently, GPC1 circulating exosomes (crExos) have been shown to be able to detect early stages of PDAC. In this study, we investigated the usefulness of crExos GPC1 as a biomarker for PDAC. Methods Plasma was obtained from patients with benign pancreatic disease ( = 16) and PDAC ( = 27) prior to pancreatectomy, and crExos were isolated by ultra-centrifugation. Protein was extracted from surgical specimens (adjacent normal pancreas, = 13; and PDAC, = 17). GPC1 levels were measured using enzyme-linked immunosorbent assay (ELISA). Results There was no significant difference in GPC1 levels between normal pancreas and PDAC tissues. This was also true when comparing matched pairs. However, GPC1 levels were enriched in PDAC crExos ( = 11), compared to the source tumors ( = 11; 97 ± 54 vs. 20.9 ± 12.3 pg/mL; 4 cm; = 0.012). Conclusions High GPC1 crExos may be able to determine PDAC tumor size and disease burden. However, further efforts are needed to elucidate its role as a diagnostic and/or prognostic biomarker using larger cohorts of PDAC patients