Neuropilin-1 in head and neck cancer

Head and neck squamous cell carcinoma (HNSCC), the sixth most common tumor worldwide, accounts for more than 550,000 new cases and 380,000 deaths per year. Patients diagnosed with locally advanced disease often require multimodal treatment approaches. Chemoradiation, with high cisplatin dose, remains the standard of care for this category of patients. Molecular target therapies have been introduced, such as the combination of the Epidermal Growth Factor Receptor (EGFR) monoclonal antibody (cetuximab) with cisplatin and 5-fluorouracil for the treatment of recurrent or metastatic HNSCC. EGFR is one of the most studied molecular target, since it is overexpressed in about 90% of HNSCC and Neuropilin-1 (Nrp-1), that is a co-receptor of EGFR, represents an interesting candidate to investigate in HNSCC. Nrp-1 has been first discovered as regulator of the nervous system development, acting together with Plexins as co-receptor for Semaphorins (SEMAs); then, Nrp-1 has been identified as receptor for several Vascular Endothelial Growth Factors (VEGFs). Recent findings determined that Nrp-1 is able to enhance the signaling activated by the ligands and tyrosine kinase receptors (RTKs) interaction. In particular, upon ligand stimulation, Nrp-1 can elicit EGFR clustering, endocytosis and signaling. Consequently, Nrp-1 results involved in multiple oncogenic processes, such as cellular proliferation, survival, invasion and migration. Few evidences reported a Nrp-1 contribution in response to cancer therapy, even if its role in chemotherapy still is in need of further investigation. In this study, we aim to address three main issues: 1) to investigate in a study population of human head and neck cancers (N=217), the Nrp-1 expression and its correlation with the clinicopathological features of patients, by statistical analysis; 2) to explore, in vitro, in stable Nrp-1 silenced head and neck cancer cells, the Nrp-1 contribution to cisplatin sensitivity; 3) to analyse the Nrp-1 role in sustaining the cisplatin-induced EGFR activation. In the HNSCC cohort of surgical samples, organized in tissue microarrays, we investigated the Nrp-1 expression by IHC analysis, showing the Nrp-1 overexpression in malignant tissues compared to the normal counterpart. Performing survival and multivariate analysis, Nrp-1 expression resulted an independent prognostic factor for HNSCC patients. By transduction with lentiviral vectors, we obtained the Nrp-1 depleted HNSCC cellular models. Interestingly, we observed the increase of cellular sensitivity to cisplatin treatment in the Nrp-1 silenced cells, compared to control cells, transduced with the empty lentiviral vector. Finally, we showed that Nrp-1 is able to sustain the cisplatin induced EGFR activation together with the tyrosine-protein kinase Src, a mechanism proposed to serve as a cell-survival response to cytotoxic stress. In conclusion, these results propose Nrp-1 as a novel prognostic marker for HNSCC. Furthermore, we provide preliminary evidences of Nrp-1 contribution to cisplatin sensitivity. Additionally, we showed, for the first time, the Nrp-1 ability to enhance the cisplatin induced EGFR activation, expanding the repertoire of signalling processes involving Nrp-1 and suggesting the need of further investigations on Nrp-1 as a suitable target for HNSCC therapies

CCDC6 (coiled-coil domain containing 6)

CCDC6 gene product is a pro-apoptotic protein substrate of ATM whose loss or inactivation enhances tumor progression. In primary tumors the impaired function of CCDC6 protein has been ascribed to CCDC6 rearrangements, to somatic mutations and to CCDC6 different levels in several neoplasia. The CCDC6 turnover is regulated in a cell cycle dependent manner upon post-translational modification events. The impairment of CCDC6 turnover may affect cells behaviour and drug response

The disruption of the CCDC6 - PP4 axis induces a BRCAness like phenotype and sensitivity to PARP inhibitors in high-grade serous ovarian carcinoma

Treatment with PARP inhibitors (PARPi) is primarily effective against high-grade serous ovarian cancers (HGSOC) with BRCA1/2 mutations or other deficiencies in homologous recombination (HR) repair mechanisms. However, resistance to PARPi frequently develops, mostly as a result of BRCA1/2 reversion mutations. The tumour suppressor CCDC6 is involved in HR repair by regulating the PP4c phosphatase activity on γH2AX. In this work, we reported that in ovarian cancer cells, a physical or functional loss of CCDC6 results synthetic lethal with the PARP-inhibitors drugs, by affecting the HR repair. We also unravelled a role for CCDC6 as predictive marker of PARPi sensitivity in ovarian cancer, and the impact of CCDC6 downregulation in overcoming PARPi resistance in these tumours

A next generation vaccine against human rabies based on a single dose of a chimpanzee adenovirus vector serotype C

Rabies, caused by RNA viruses in the Genus Lyssavirus, is the most fatal of all infectious diseases. This neglected zoonosis remains a major public health problem in developing countries, causing the death of an estimated 25,000-159,000 people each year, with more than half of them in children. The high incidence of human rabies in spite of effective vaccines is mainly linked to the lack of compliance with the complicated administration schedule, inadequacies of the community public health system for local administration by the parenteral route and the overall costs of the vaccine. The goal of our work was the development of a simple, affordable and effective vaccine strategy to prevent human rabies virus infection. This next generation vaccine is based on a replication-defective chimpanzee adenovirus vector belonging to group C, ChAd155-RG, which encodes the rabies glycoprotein (G). We demonstrate here that a single dose of this vaccine induces protective efficacy in a murine model of rabies challenge and elicits strong and durable neutralizing antibody responses in vaccinated non-human primates. Importantly, we demonstrate that one dose of a commercial rabies vaccine effectively boosts the neutralizing antibody responses induced by ChAd155-RG in vaccinated monkeys, showing the compatibility of the novel vectored vaccine with the current post-exposure prophylaxis in the event of rabies virus exposure. Finally, we demonstrate that antibodies induced by ChAd155-RG can also neutralize European bat lyssaviruses 1 and 2 (EBLV-1 and EBLV-2) found in bat reservoirs

Caffeine Prevents Transcription Inhibition and P-TEFb/7SK Dissociation Following UV-Induced DNA Damage

Background: The mechanisms by which DNA damage triggers suppression of transcription of a large number of genes are poorly understood. DNA damage rapidly induces a release of the positive transcription elongation factor b (P-TEFb) from the large inactive multisubunit 7SK snRNP complex. P-TEFb is required for transcription of most class II genes through stimulation of RNA polymerase II elongation and cotranscriptional pre-mRNA processing. Methodology/Principal Findings: We show here that caffeine prevents UV-induced dissociation of P-TEFb as well as transcription inhibition. The caffeine-effect does not involve PI3-kinase-related protein kinases, because inhibition of phosphatidylinositol 3-kinase family members (ATM, ATR and DNA-PK) neither prevents P-TEFb dissociation nor transcription inhibition. Finally, caffeine prevention of transcription inhibition is independent from DNA damage. Conclusion/Significance: Pharmacological prevention of P-TEFb/7SK snRNP dissociation and transcription inhibitio

Antimicrobial resistance among migrants in Europe: a systematic review and meta-analysis

BACKGROUND: Rates of antimicrobial resistance (AMR) are rising globally and there is concern that increased migration is contributing to the burden of antibiotic resistance in Europe. However, the effect of migration on the burden of AMR in Europe has not yet been comprehensively examined. Therefore, we did a systematic review and meta-analysis to identify and synthesise data for AMR carriage or infection in migrants to Europe to examine differences in patterns of AMR across migrant groups and in different settings. METHODS: For this systematic review and meta-analysis, we searched MEDLINE, Embase, PubMed, and Scopus with no language restrictions from Jan 1, 2000, to Jan 18, 2017, for primary data from observational studies reporting antibacterial resistance in common bacterial pathogens among migrants to 21 European Union-15 and European Economic Area countries. To be eligible for inclusion, studies had to report data on carriage or infection with laboratory-confirmed antibiotic-resistant organisms in migrant populations. We extracted data from eligible studies and assessed quality using piloted, standardised forms. We did not examine drug resistance in tuberculosis and excluded articles solely reporting on this parameter. We also excluded articles in which migrant status was determined by ethnicity, country of birth of participants' parents, or was not defined, and articles in which data were not disaggregated by migrant status. Outcomes were carriage of or infection with antibiotic-resistant organisms. We used random-effects models to calculate the pooled prevalence of each outcome. The study protocol is registered with PROSPERO, number CRD42016043681. FINDINGS: We identified 2274 articles, of which 23 observational studies reporting on antibiotic resistance in 2319 migrants were included. The pooled prevalence of any AMR carriage or AMR infection in migrants was 25·4% (95% CI 19·1-31·8; I2 =98%), including meticillin-resistant Staphylococcus aureus (7·8%, 4·8-10·7; I2 =92%) and antibiotic-resistant Gram-negative bacteria (27·2%, 17·6-36·8; I2 =94%). The pooled prevalence of any AMR carriage or infection was higher in refugees and asylum seekers (33·0%, 18·3-47·6; I2 =98%) than in other migrant groups (6·6%, 1·8-11·3; I2 =92%). The pooled prevalence of antibiotic-resistant organisms was slightly higher in high-migrant community settings (33·1%, 11·1-55·1; I2 =96%) than in migrants in hospitals (24·3%, 16·1-32·6; I2 =98%). We did not find evidence of high rates of transmission of AMR from migrant to host populations. INTERPRETATION: Migrants are exposed to conditions favouring the emergence of drug resistance during transit and in host countries in Europe. Increased antibiotic resistance among refugees and asylum seekers and in high-migrant community settings (such as refugee camps and detention facilities) highlights the need for improved living conditions, access to health care, and initiatives to facilitate detection of and appropriate high-quality treatment for antibiotic-resistant infections during transit and in host countries. Protocols for the prevention and control of infection and for antibiotic surveillance need to be integrated in all aspects of health care, which should be accessible for all migrant groups, and should target determinants of AMR before, during, and after migration. FUNDING: UK National Institute for Health Research Imperial Biomedical Research Centre, Imperial College Healthcare Charity, the Wellcome Trust, and UK National Institute for Health Research Health Protection Research Unit in Healthcare-associated Infections and Antimictobial Resistance at Imperial College London

Correction: A next generation vaccine against human rabies based on a single dose of a chimpanzee adenovirus vector serotype C.

[This corrects the article DOI: 10.1371/journal.pntd.0008459.]

Surgical site infection after gastrointestinal surgery in high-income, middle-income, and low-income countries: a prospective, international, multicentre cohort study

Background: Surgical site infection (SSI) is one of the most common infections associated with health care, but its importance as a global health priority is not fully understood. We quantified the burden of SSI after gastrointestinal surgery in countries in all parts of the world. Methods: This international, prospective, multicentre cohort study included consecutive patients undergoing elective or emergency gastrointestinal resection within 2-week time periods at any health-care facility in any country. Countries with participating centres were stratified into high-income, middle-income, and low-income groups according to the UN's Human Development Index (HDI). Data variables from the GlobalSurg 1 study and other studies that have been found to affect the likelihood of SSI were entered into risk adjustment models. The primary outcome measure was the 30-day SSI incidence (defined by US Centers for Disease Control and Prevention criteria for superficial and deep incisional SSI). Relationships with explanatory variables were examined using Bayesian multilevel logistic regression models. This trial is registered with ClinicalTrials.gov, number NCT02662231. Findings: Between Jan 4, 2016, and July 31, 2016, 13 265 records were submitted for analysis. 12 539 patients from 343 hospitals in 66 countries were included. 7339 (58·5%) patient were from high-HDI countries (193 hospitals in 30 countries), 3918 (31·2%) patients were from middle-HDI countries (82 hospitals in 18 countries), and 1282 (10·2%) patients were from low-HDI countries (68 hospitals in 18 countries). In total, 1538 (12·3%) patients had SSI within 30 days of surgery. The incidence of SSI varied between countries with high (691 [9·4%] of 7339 patients), middle (549 [14·0%] of 3918 patients), and low (298 [23·2%] of 1282) HDI (p < 0·001). The highest SSI incidence in each HDI group was after dirty surgery (102 [17·8%] of 574 patients in high-HDI countries; 74 [31·4%] of 236 patients in middle-HDI countries; 72 [39·8%] of 181 patients in low-HDI countries). Following risk factor adjustment, patients in low-HDI countries were at greatest risk of SSI (adjusted odds ratio 1·60, 95% credible interval 1·05–2·37; p=0·030). 132 (21·6%) of 610 patients with an SSI and a microbiology culture result had an infection that was resistant to the prophylactic antibiotic used. Resistant infections were detected in 49 (16·6%) of 295 patients in high-HDI countries, in 37 (19·8%) of 187 patients in middle-HDI countries, and in 46 (35·9%) of 128 patients in low-HDI countries (p < 0·001). Interpretation: Countries with a low HDI carry a disproportionately greater burden of SSI than countries with a middle or high HDI and might have higher rates of antibiotic resistance. In view of WHO recommendations on SSI prevention that highlight the absence of high-quality interventional research, urgent, pragmatic, randomised trials based in LMICs are needed to assess measures aiming to reduce this preventable complication

Neuropilins Controlling Cancer Therapy Responsiveness

Neuropilins (NRPs) are cell surface glycoproteins, acting as co-receptors for secreted Semaphorins (SEMAs) and for members of the vascular endothelial growth factor (VEGF) family; they have been initially implicated in axon guidance and angiogenesis regulation, and more recently in cancer progression. In addition, NRPs have been shown to control many other fundamental signaling pathways, especially mediated by tyrosine kinase receptors (RTKs) of growth factors, such as HGF (hepatocyte growth factor), PDGF (platelet derived growth factor) and EGF (epidermal growth factor). This enables NRPs to control a range of pivotal mechanisms in the cancer context, from tumor cell proliferation and metastatic dissemination, to tumor angiogenesis and immune escape. Moreover, cancer treatment failures due to resistance to innovative oncogene-targeted drugs is typically associated with the activity of alternative RTK-dependent pathways; and neuropilins&#8217; capacity to control oncogenic signaling cascades supports the hypothesis that they could elicit such mechanisms in cancer cells, in order to escape cytotoxic stress and therapeutic attacks. Intriguingly, several studies have recently assayed the impact of NRPs inhibition in combination with diverse anti-cancer drugs. In this minireview, we will discuss the state-of-art about the relevance of NRPs as potential predictive biomarkers of drug response, and the rationale to target these proteins in combination with other anticancer therapies