The emergence of a new influenza pandemic remains a threat that could result in a substantial loss of life and economic disruption worldwide. Advances in human antibody isolation have led to the ...discovery of monoclonal antibodies (mAbs) that have broad neutralizing activity against various influenza strains, although their direct use for prophylaxis is impractical. To overcome this limitation, our approach is to deliver antibody via adeno-associated virus (AAV) vectors to the site of initial infection, which, for respiratory viruses such as influenza, is the nasopharyngeal mucosa. AAV vectors based on serotype 9 were engineered to express a modified version of the previously isolated broadly neutralizing mAb to influenza A, FI6. We demonstrate that intranasal delivery of AAV9.FI6 into mice afforded complete protection and log reductions in viral load to 100 LD₅₀ (median lethal dose) of three clinical isolates of H5N1 and two clinical isolates of H1N1, all of which have been associated with historic human pandemics (including H1N1 1918). Similarly, complete protection was achieved in ferrets challenged with lethal doses of H5N1 and H1N1. This approach serves as a platform for the prevention of natural or deliberate respiratory diseases for which a protective antibody is available.
Infants and older adults are especially vulnerable to infection by respiratory syncytial virus (RSV), which can cause significant illness and irreparable damage to the lower respiratory tract and for ...which an effective vaccine is not readily available. Palivizumab, a recombinant monoclonal antibody (mAb), is an approved therapeutic for RSV infection for use in high-risk infants only. Due to several logistical issues, including cost of goods and scale-up limitations, palivizumab is not approved for other populations that are vulnerable to severe RSV infections, such as older adults. In this study, we demonstrate that intranasal delivery of adeno-associated virus serotype 9 (AAV9) vector expressing palivizumab or motavizumab, a second-generation version of palivizumab, significantly reduced the viral load in the lungs of the BALB/c mouse model of RSV infection. Notably, we demonstrate that AAV9 vector-mediated prophylaxis against RSV was effective despite the presence of serum-circulating neutralizing AAV9 antibodies. These findings substantiate the feasibility of repeatedly administering AAV9 vector to the airway for seasonal prophylaxis against RSV, thereby expanding the application of vectored delivery of mAbs as an effective prophylaxis strategy against various airborne viruses.
Propose This study aimed to propose an innovative, open, and circular program that combines acceptance and commitment therapy (ACT) and mindfulness practices. We assessed its feasibility, ...acceptability, and first signs of its effect on psychological wellbeing in cancer support treatment. Methods A single-center, single-arm, uncontrolled study was performed. Forty adult patients with non-metastatic prostate or breast cancer, newly diagnosed or undergoing treatment (chemotherapy, radiotherapy, hormone therapy), were recruited. Three cycles of three MAEva program sessions (MAEva: Mindfulness meditation, Acceptance, and Commitment to values program) over nine consecutive weeks were proposed. During the total of 12 weeks of follow-up, after attending the first session, patients were free to attend subsequent sessions. Results Adherence to the study was high, with participation in an average of 6.8 out of nine sessions. A total of eight patients attended all sessions over the three cycles, and 90% participated in at least one cycle. Furthermore, attendance was associated with a statistically significant improvement in Quality of Life (QoL). Each additional session was associated with a mean increase in overall QoL score of more than one point (β = 1.09 0.13; 2.04, p = 0.02). The fatigue dimensions decreased with session attendance: physical (β = −2.24 −3.63; −0.85), emotional (β = −2.60 −4.11; −1.09), and interference with daily life (β = −2.33 −3.95; −0.72). The qualitative section demonstrated that patients learned skills and shared their ability to “let go”. Patients rated the degree of importance of the program at 8.36/10 (SD ± 1.64). Conclusion This study highlights the feasibility and acceptability of an original program that combines ACT and mindfulness practices in cancer patients. Future studies are required to demonstrate the efficacy of the MAEVA program. The MAEva pilot study is registered with ClinicalTrials.gov under the identifier NCT04751201. Clinical trial registration https://classic.clinicaltrials.gov/ct2/show/NCT04751201 , identifier NCT04751201.
Surgery is a cornerstone of breast cancer management. Prior to surgery, a wire marker is placed at the site of the tumor, to enable the surgeon to accurately localize the lesion during later surgery. ...This procedure can generate considerable anxiety for many patients. We investigated the value of conversational hypnosis (CH) in reducing anxiety in patients undergoing preoperative wire placement under radiographic control.
Randomized, multicentre study in 7 centers in France. Inclusion criteria were patients aged >18 years with an Eastern Cooperative Oncology Group performance status ≤2, scheduled to undergo preoperative wire placement in one or several breast lesions. Patients were randomized in a 1:1 ratio, stratified by center to undergo preoperative wire placement with or without the use of CH by a radiological technician trained in the CH technique. The primary endpoint was the percentage of patients with an anxiety score ≥ 6 on a visual analog scale ranging from 0 (absence of anxiety) to 10 (maximal anxiety). Secondary endpoints were pain score, perceived duration reported by the patient, technician satisfaction with their relationship with the patient, and ease of marker insertion reported by the radiologist. Semi-structured interviews were performed with patients to assess their perception of the marker placement procedure.
The trial was prematurely interrupted for futility after a planned interim analysis after accrual of 167 patients, i.e., half the planned sample size. Prior to marker placement, 29.3% (
= 24) of patients in the control group had an anxiety score ≥ 6, versus 42.3% (
= 33) in the CH group (
= 0.08). After marker placement, the change of anxiety score was not significantly different between groups (11.0% (
= 9) versus 14.3% (
= 11),
= 0.615). There was no significant difference in any of the secondary endpoints. In the interviews, patients from both groups frequently spoke of a feeling of trust.
This study failed to show a benefit of conversational hypnosis on anxiety in patients undergoing marker placement prior to surgery for breast cancer. The fact that some caregivers had learned this personalized therapeutic communication technique may have had a positive impact on the whole caregiving team.
The study was registered with ClinicalTrials.gov (NCT02867644).
Influenza causes serious and sometimes fatal disease in individuals at risk due to advanced age or immunodeficiencies. Despite progress in the development of seasonal influenza vaccines, vaccine ...efficacy in elderly and immunocompromised individuals remains low. We recently developed a passive immunization strategy using an adeno-associated virus (AAV) vector to deliver a neutralizing anti-influenza antibody at the site of infection, the nasal airways. Here we show that young, old, and immunodeficient (severe combined immunodeficient SCID) mice that were treated intranasally with AAV9 vector expressing a modified version of the broadly neutralizing anti-influenza antibody FI6 were protected and exhibited no signs of disease following an intranasal challenge with the mouse-adapted H1N1 influenza strain A/Puerto Rico/8/1934(H1N1) (PR8) (Mt. Sinai strain). Nonvaccinated mice succumbed to the PR8 challenge due to severe weight loss. We propose that airway-directed AAV9 passive immunization against airborne infectious agents may be beneficial in elderly and immunocompromised patients, for whom there still exists an unmet need for effective vaccination against influenza.
Purpose: Replication-selective oncolytic adenoviruses are a promising class of tumor-targeting agents with proven safety in hundreds
of patients. However, clinical responses have been limited and ...viral mutants with higher potency are needed. Here, we report
on the generation of a novel set of mutants with improved efficacy in prostate and pancreatic carcinoma models. Currently,
no curative treatments are available for late-stage metastatic prostate or rapidly progressing pancreatic cancers.
Experimental Design: Adenovirus type 5 mutants were created with deletions in the E1ACR2 region for tumor selectivity and/or the E1B19K gene for attenuated replication in vivo ; all constructs retain the E3 genes intact. Cell-killing efficacy, replication, and cytotoxicity in combination with chemotherapeutics were investigated
in normal cells (PrEC and NHBE), seven carcinoma cell lines, and human (PC3 and DU145) and murine (TRAMPC, CMT-64, and CMT-93)
tumor models in vivo .
Results: The double-deleted AdΔΔ (ΔE1ACR2 and ΔE1B19K) mutant had high cell-killing activity in prostate, pancreatic, and lung carcinomas.
Replication was similar to wild-type in all tumor cells and was attenuated in normal cells to levels less than the single-deleted
AdΔCR2 mutant. AdΔΔ combined with the chemotherapeutics docetaxel and mitoxantrone resulted in synergistically enhanced cell
killing and greatly improved antitumor efficacy in prostate xenografts in vivo . In murine immunocompetent in vivo models efficacy was greater for mutants with the E3B genes intact even in the absence of viral replication, indicating attenuated macrophage-dependent clearance.
Conclusions: These data suggest that the novel oncolytic mutant AdΔΔ is a promising candidate for targeting of solid tumors specifically
in combination with chemotherapeutics. Clin Cancer Res; 16(2); 541–53
The complete nucleotide sequence of an isolate of simian adenovirus 7 (SAdV-7) was determined. The genome organization of this isolate was found to be similar to that of other primate adenoviruses ...with two principal notable points: severe truncation of the E1A and E1B 19K proteins and an E3 region encoding only the 12.5K homologue. The viral gene products of SAdV-7 are most closely related to simian adenovirus 1 (SAdV-1), and like SAdV-1, are related to the human adenovirus species HAdV-F, such as the enteric adenoviruses HAdV-40 and HAdV-41 and the recently defined HAdV-G (HAdV-52). Two kinds of gene transfer vectors were made: a replication-competent SAdV-7-based vector with no genomic deletion, and a standard replication-incompetent vector deleted for E1. Importantly, the E1-deleted vector could be propagated to high titre by trans-complementation in human HEK 293 cells.
Smaug est le dragon maléfique voleur de trésor et principal antagoniste du roman The Hobbit (1937), premier texte publié de Tolkien à mettre en scène la Terre du Milieu. Universitaire et poète, il ...tire son inspiration de textes médiévaux anglais et norrois, écrits par des Scandinaves ou évoquant le Nord : Smaug ressemble fort à Fáfnir, le monstre tué par le héros Sigurðr, et au dragon de Beowulf . Tolkien a réutilisé certaines caractéristiques de ces œuvres mais au lieu de les rapporter à leur espace originel, la Scandinavie, il s’en sert pour créer un lieu fictionnel.Dans cet article, on examinera les implications liées à l’utilisation d’éléments boréalistes dans un roman fantasy , en utilisant Smaug comme étude de cas. Quels traits thématiques et rhétoriques Tolkien a-t-il emprunté à la description de ces dragons nordiques ? Quelles conséquences entraîne le recourt à ces éléments boréalistes déconnectés de leur référent géographique originel ?
Ischemic preconditioning (IPC; brief cycles of coronary occlusion/ reperfusion) reduces myocardial infarct size. The ST-segment elevation during coronary occlusion is progressively attenuated with ...increasing number of IPC cycles. Progressive attenuation of ST-segment elevation is considered a result of sarcolemmal KATP channel activation and has been considered to reflect and predict IPC's cardioprotection. We have recently demonstrated that IPC failed to reduce infarct size in minipigs of a particular strain (Ossabaw), which had a genetic predisposition to develop, but not yet established a metabolic syndrome. To determine whether or not Ossabaw minipigs nevertheless had attenuated ST-segment elevation over repetitive IPC cycles, we compared Göttingen vs. Ossabaw minipigs in which IPC reduces infarct size.
We analyzed surface chest electrocardiographic (ECG) recordings of anesthetized open-chest contemporary Göttingen (n = 43) and Ossabaw minipigs (n = 53). Both minipig strains were subjected to 60 min coronary occlusion and 180 min reperfusion without or with IPC (3 × 5 min/ 10 min coronary occlusion/ reperfusion). ST-segment elevations during the repetitive coronary occlusions were analyzed. In both minipig strains, IPC attenuated ST-segment elevation with increasing number of coronary occlusions. IPC reduced infarct size in Göttingen minipigs (45 ± 10% without vs. 25 ± 13% of area at risk with IPC), whereas such cardioprotection was absent in Ossabaw minipigs (54 ± 11% vs. 50 ± 11%).
Apparently, the block of signal transduction of IPC in Ossabaw minipigs occurs distal to the sarcolemma, where KATP channel activation still attenuates ST-segment elevation as it does in Göttingen minipigs.
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•Progressive attenuation of ST-segment elevation with repetitive coronary occlusions reflects cardioprotection by ischemic preconditioning (IPC) and is attributed to sarcolemmal KATP channel activation.•IPC does not reduce infarct size in Ossabaw minipigs, in contrast to the established infarct size reduction in Göttingen minipigs.•Progressive attenuation of ST-segment elevation with repetitive coronary occlusions occurs in both strains.•The block of cardioprotective IPC signaling in Ossabaw minipigs occurs distal to the sarcolemma.•Progressive attenuation of ST-segment elevation with repetitive coronary occlusions is an unreliable reflection of cardioprotection.
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