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BackgroundNeuropilin (NRP) is a transmembrane protein, which has been shown to be a pro-angiogenic mediator and implicated as a potential driver of cancer progression. NRP-1 up-regulation in ovarian cancer tissue predicts poor prognosis. However, the clinical relevance of the soluble form of NRP-1 (sNRP-1) as a circulating biomarker in ovarian cancer patients is unknown.Methods/patients cohortsNRP-1 levels were quantified in a cohort of 88 clinically documented ovarian cancer patients by a commercially available sNRP-1 enzyme-linked immunosorbent assay (ELISA) kit (Biomedica, Vienna, Austria). Patients (81.8% with FIGOIII/IV) received primary cytoreductive surgery with the aim of macroscopic complete resection (achieved in 55.7% of patients) and the recommendation of adjuvant chemotherapy in line with national guidelines.ResultsHigher levels of sNRP-1 reflected more advanced disease (FIGO III/IV) and indicated a trend towards suboptimal surgical outcome, i.e. any residual tumor. sNRP-1 was neither related to the patients’ age nor the BRCA1/2 mutational status. Patients with higher sNRP-1 levels at primary diagnosis had a significantly reduced progression-free survival (PFS) (HR = 0.541, 95%CI: 0.304 - 0.963; p = 0.037) and overall survival (OS) (HR = 0.459, 95%CI: 0.225 - 0.936; p = 0.032). Principal component analysis showed that sNRP-1 levels were unrelated to the circulating hepatocyte growth factor (HGF) and the soluble ectodomain of its receptor the tyrosine kinase mesenchymal–epithelial transition (c-MET), suggesting that there is no proportional serological concentration gradient of soluble components of the NRP-1/HGF/c-MET signaling axis.ConclusionsIn line with the previously shown tissue-based prognostic role, we demonstrated for the first time that sNRP-1 can also act as a readily accessible, prognostic biomarker in the circulation of patients with ovarian cancer at primary diagnosis. Given its known role in angiogenesis and conferring resistance to the poly ADP-ribose polymerase (PARP) inhibitor olaparib in vitro, our results encourage more detailed investigation into sNRP-1 as a potential predictive biomarker for bevacizumab and/or PARP-inhibitor treatment.

Abstract Molecular Nanomagnets may enable the implementation of qudit-based quantum error-correction codes which exploit the many spin levels naturally embedded in a single molecule, a promising step towards scalable quantum processors. To fully realize the potential of this approach, a microscopic understanding of the errors corrupting the quantum information encoded in a molecular qudit is essential, together with the development of tailor-made quantum error correction strategies. We address these central points by first studying dephasing effects on the molecular spin qudit produced by the interaction with surrounding nuclear spins, which are the dominant source of errors at low temperatures. Numerical quantum error correction codes are then constructed, by means of a systematic optimization procedure based on simulations of the coupled system-bath dynamics, that provide a striking enhancement of the coherence time of the molecular computational unit. The sequence of pulses needed for the experimental implementation of the codes is finally proposed.

BackgroundRucaparib, a poly(ADP-ribose) polymerase inhibitor, has anticancer activity in recurrent ovarian carcinoma harbouring a BRCA mutation or high percentage of genome-wide loss of heterozygosity. In this trial we assessed rucaparib versus placebo after response to second-line or later platinum-based chemotherapy in patients with high-grade, recurrent, platinum-sensitive ovarian carcinoma.MethodsIn this randomised, double-blind, placebo-controlled, phase 3 trial, we recruited patients from 87 hospitals and cancer centres across 11 countries. Eligible patients were aged 18 years or older, had a platinum-sensitive, high-grade serous or endometrioid ovarian, primary peritoneal, or fallopian tube carcinoma, had received at least two previous platinum-based chemotherapy regimens, had achieved complete or partial response to their last platinum-based regimen, had a cancer antigen 125 concentration of less than the upper limit of normal, had a performance status of 0-1, and had adequate organ function. Patients were ineligible if they had symptomatic or untreated central nervous system metastases, had received anticancer therapy 14 days or fewer before starting the study, or had received previous treatment with a poly(ADP-ribose) polymerase inhibitor. We randomly allocated patients 2:1 to receive oral rucaparib 600 mg twice daily or placebo in 28 day cycles using a computer-generated sequence (block size of six, stratified by homologous recombination repair gene mutation status, progression-free interval after the penultimate platinum-based regimen, and best response to the most recent platinum-based regimen). Patients, investigators, site staff, assessors, and the funder were masked to assignments. The primary outcome was investigator-assessed progression-free survival evaluated with use of an ordered step-down procedure for three nested cohorts: patients with BRCA mutations (carcinoma associated with deleterious germline or somatic BRCA mutations), patients with homologous recombination deficiencies (BRCA mutant or BRCA wild-type and high loss of heterozygosity), and the intention-to-treat population, assessed at screening and every 12 weeks thereafter. This trial is registered with ClinicalTrials.gov, number NCT01968213; enrolment is complete.FindingsBetween April 7, 2014, and July 19, 2016, we randomly allocated 564 patients: 375 (66%) to rucaparib and 189 (34%) to placebo. Median progression-free survival in patients with a BRCA-mutant carcinoma was 16·6 months (95% CI 13·4-22·9; 130 [35%] patients) in the rucaparib group versus 5·4 months (3·4-6·7; 66 [35%] patients) in the placebo group (hazard ratio 0·23 [95% CI 0·16-0·34]; p

Abstract The aim of this study was to detect a parameter for predicting prenatal complications or postnatal surgical options after detecting a fetal exomphalos. This was a retrospective analysis of prenatal diagnosis and outcome of fetuses with 41 cases of exomphalos in between 2007 and 2017, considering the measurement of ratios. The 41 fetuses with exomphalos were examined, 34 cases (82.9%) with karyotyping and 16 cases (39%) with an abnormal karyotype. Outcome of 39 cases showed 6 abortions (15.4%), 15 terminations (38.5%), an intrauterine fetal death (2.5%) and 17 alive babies (43.6%), which were grouped in two: small exomphalos (n = 6, 35.3%) and big exomphalos (n = 11, 64.7%). Maximal diameter of exomphalos/abdomen circumference-ratio (EDmax/AC-ratio) with a cut-off of 0.24 showed a better predictive value of postnatal primary closure. Exomphalos is correlated with abnormal karyotype. EDmax/AC-ratio gives the best prediction for postnatal primary closure of the defect.

Mountain glaciers and snowfields are rapidly receding because of climate warming. Species living in these habitats remain poorly studied, likely because of the remoteness and ruggedness of their terrain. We leveraged community science data from eBird—an online database of bird observations from around the world—to characterize bird use of mountain glaciers and snowfields. We estimated total bird biodiversity and preference for glaciers and snowfields over nearby, ice-adjacent habitats. We used field notes from eBird users and breeding codes to extend our data set to include insight into habitat usage and behavior. Finally, we compared our community-science approach to previous studies that used traditional (i.e., professional) field survey methods. We identified considerable avian biodiversity in glacier and snowfield habitat (46 species) with four specialists that appeared to prefer glaciers and snowfields over nearby, ice-adjacent habitats. Birds appeared to primarily use the glacier and snowfield habitats for foraging. When community science data was compared to traditional methods, results were similar, but community science resulted in a higher species diversity estimate. Our findings suggest glacier and snowfield retreat threatens specialist species via loss of nutrient resources. Additionally, community science data appears valuable for characterizing difficult to access areas, but traditional surveys are still useful for more rigorous quantification of avian biodiversity.

Abstract Background Physical training is recommended in various national and international guidelines for patients with cancer. Observational studies have shown that physical activity leads to reduced recurrence and mortality rates by 20–40% in colorectal, breast, and prostate cancer. Despite existing evidence, a systematic care structure is still lacking. The primary aim of this study is to implement and evaluate an online training platform to strengthen physical performance and patient empowerment after cancer surgery. Methods The evaluation will be conducted as a prospective multicenter randomized controlled trial with three subgroups (colorectal-, breast-, and prostate cancer). Each group will include 100 patients (total 300 patients including dropouts; clinical stages T1–3 and/or N+; M0 after surgery intervention) and the primary endpoint (13% increase in the maximal oxygen consumption during exercise) will be examined. The intervention group will receive a 6-month home-based online training (2–3 times per week strength-endurance training using video presentations), bidirectional activity feedback information, online communication, and online counseling. The control group (usual care) will be advised lifestyle improvement. In-hospital testing will be performed before, during, and after the intervention. In addition to cardiopulmonary capacity, tumor specific diagnostics (liquid biopsy, depression and fatigue assessment, metabolic and endothelial screening) will be applied. Discussion Due to the increasing incidence of cancer, associated with considerable mortality, morbidity and impaired quality of life, there is an imperative requirement for improved cancer care, of which structured physical training may become an integral component. Trial registration DRKS-ID: DRKS00020499 ; Registered 17 March 2020.

Genome engineering in cell lines or human stem cells often has poor efficiency, limiting the development of research and therapeutic applications. Here, the authors use a toxin-based selection system for precise bi-allelic engineering in cells and in vivo.

Purpose: Treatment with CDK4/6 inhibitors and endocrine therapy (CDK4/6i + ET) is a standard for patients with advanced hormone receptor–positive, HER2-negative (HR + HER2–) breast cancer (BC). However, real-world data on the implementation of therapy usage, efficacy, and toxicity have not yet been reported. Methods: The PRAEGNANT registry was used to identify advanced HR + HER2– BC patients (n = 1136). The use of chemotherapy, ET, everolimus + ET, and CDK4/6i + ET was analyzed for first-line, second-line, and third-line therapy. Progression-free survival (PFS) and overall survival (OS) were also compared between patients treated with CDK4/6i + ET and ET monotherapy. Also toxicity was assessed. Results: CDK4/6i + ET use increased from 38.5% to 62.7% in the first 2 years after CDK4/6i treatment became available (November 2016). Chemotherapy and ET monotherapy use decreased from 2015 to 2018 from 42.2% to 27.2% and from 53% to 9.5%, respectively. In this early analysis no statistically significant differences were found comparing CDK4/6i + ET and ET monotherapy patients with regard to PFS and OS. Leukopenia was was seen in 11.3% of patients under CDK4/6i + ET and 0.5% under ET monotherapy. Conclusions: In clinical practice, CDK4/6i + ET has been rapidly implemented. A group of patients with a more unfavorable prognosis was possibly treated in the real-world setting than in the reported randomized clinical trials. The available data suggest that longer follow-up times and a larger sample size are required in order to identify differences in survival outcomes. Studies should be supported that investigate whether chemotherapy can be avoided or delayed in this patient population by using CDK4/6i + ET.

CRISPR/Cas9 technology has revolutionised the ability of scientists to make genetically modified cells and animal models. Here, the authors make a Tet-On genetically modified mouse using the Streptococcus pyogenes Cas9 and demonstrate that it can be used for generation of mice with lung cancer.

Abstract Background Ovarian cancer remains the most fatal gynecological malignancy. Current therapeutic options are limited due to late diagnosis in the majority of the cases, metastatic spread to the peritoneal cavity and the onset of chemo-resistance. Thus, novel therapeutic approaches are required. Statins and amino-bisphosphonates are inhibitors of the mevalonate pathway, which is a fundamental pathway of cellular metabolism, essential for cholesterol production and posttranslational protein farnesylation and geranylgeranylation. While this pathway has emerged as a promising treatment target in several human malignancies, its potential as a therapeutic approach in ovarian cancer is still not fully understood. Methods Human ovarian cancer cell lines (IGROV-1, A2780, A2780cis) were treated with increasing concentrations (0.5-100 μM) of statins (simvastatin, atorvastatin, rosuvastatin) and zoledronic acid. Effects on cell vitality and apoptosis were assessed using Cell Titer Blue®, Caspase 3/7 Glo®, clonogenic assays as well as cleaved poly (ADP-ribose) polymerase (cPARP) detection. The inhibition of the mevalonate pathway was confirmed using Western Blot of unprenylated Ras and Rap1a proteins. Quantitative real-time PCR and ELISA were used to analyze modulations on several key regulators of ovarian cancer tumorigenesis. Results The treatment of IGROV-1 and A2780 cells with statins and zoledronic acid reduced vitality (by up to 80%; p

Platinum‐based compounds remain a well‐established chemotherapy for cancer treatment despite their adverse effects which substantially restrict the therapeutic windows of the drugs. Both the cell type‐specific toxicity and the clinical responsiveness of tumors have been associated with mechanisms that alter drug entry and export. We sought to identify pharmacological agents that promote cisplatin (CP) efficacy by augmenting the levels of drug‐induced DNA lesions in malignant cells and simultaneously protecting normal tissues from accumulating such damage and from functional loss. Formation and persistence of platination products in the DNA of individual nuclei were measured in drug‐exposed cell lines, in primary human tumor cells and in tissue sections using an immunocytochemical method. Using a mouse model of CP‐induced toxicity, the antihistaminic drug diphenhydramine (DIPH) and two methylated derivatives decreased DNA platination in normal tissues and also ameliorated nephrotoxicity, ototoxicity, and neurotoxicity. In addition, DIPH sensitized multiple cancer cell types, particularly ovarian cancer cells, to CP by increasing intracellular uptake, DNA platination, and/or apoptosis in cell lines and in patient‐derived primary tumor cells. Mechanistically, DIPH diminished transport capacity of CP efflux pumps MRP2, MRP3, and MRP5 particularly in its C2+C6 bimethylated form. Overall, we demonstrate that DIPH reduces side effects of platinum‐based chemotherapy and simultaneously inhibits key mechanisms of platinum resistance. We propose that measuring DNA platination after ex vivo exposure may predict the responsiveness of individual tumors to DIPH‐like modulators.