Improved induction of anti-melanoma T cells by adenovirus-5/3 fiber modification to target human DCs

To mount a strong anti-tumor immune response, non T cell inflamed (cold) tumors may require combination treatment encompassing vaccine strategies preceding checkpoint inhibition. In vivo targeted delivery of tumor-associated antigens (TAA) to dendritic cells (DCs), relying on the natural functions of primary DCs in situ, represents an attractive vaccination strategy. In this study we made use of a full-length MART-1 expressing C/B-chimeric adenoviral vector, consisting of the Ad5 capsid and the Ad3 knob (Ad5/3), which we previously showed to selectively transduce DCs in human skin and lymph nodes. Our data demonstrate that chimeric Ad5/3 vectors encoding TAA, and able to target human DCs in situ, can be used to efficiently induce expansion of functional tumor-specific CD8⁺ effector T cells, either from a naïve T cell pool or from previously primed T cells residing in the melanoma-draining sentinel lymph nodes (SLN). These data support the use of Ad3-knob containing viruses as vaccine vehicles for in vivo delivery. "Off-the-shelf" DC-targeted Ad vaccines encoding TAA could clearly benefit future immunotherapeutic approaches

An epidemiological, developmental and clinical overview of cannabis use during pregnancy

The objective of the current narrative literature review is to provide an epidemiological, developmental and clinical overview on cannabis use during pregnancy. Cannabis use in pregnancy poses major health concerns for pregnant mothers and their developing children. Although studies on the short- and long-term consequences of prenatal cannabis exposure are increasing, findings have been inconsistent or difficult to interpret due to methodological issues. Thus, consolidating these findings into clinical recommendations based on the mixed studies in the literature remains a challenge. Synthesizing the available observational studies is also difficult, because some of the published studies have substantial methodological weaknesses. Improving observational studies will be an important step toward understanding the extent to which prenatal exposure to cannabis influences neurodevelopment in the offspring. Therefore, further research on prenatal cannabis exposure and the long-term consequences to offspring health in representative samples are needed to guide and improve clinical care for pregnant women and their children. Future research should also investigate the role of policies on prenatal cannabis use

Monitoring of Biodistribution and Persistence of Conditionally Replicative Adenovirus in a Murine Model of Ovarian Cancer Using Capsid-Incorporated mCherry and Expression of Human Somatostatin Receptor Subtype 2 Gene

A significant limiting factor to the human clinical application of conditionally replicative adenovirus (CRAd)-based virotherapy is the inability to noninvasively monitor these agents and their potential persistence. To address this issue, we proposed a novel imaging approach that combines transient expression of the human somatostatin receptor (SSTR) subtype 2 reporter gene with genetic labeling of the viral capsid with mCherry fluorescent protein. To test this dual modality system, we constructed the Ad5/3Δ24pIXcherry/SSTR CRAd and validated its capacity to generate fluorescent and nuclear signals in vitro and following intratumoral injection. Analysis of 64 Cu-CB-TE2A-Y3-TATE biodistribution in mice revealed reduced uptake in tumors injected with the imaging CRAd relative to the replication-incompetent, Ad-expressing SSTR2 but significantly greater uptake compared to the negative CRAd control. Optical imaging demonstrated relative correlation of fluorescent signal with virus replication as determined by viral genome quantification in tumors. Positron emission tomography/computed tomography studies demonstrated that we can visualize radioactive uptake in tumors injected with imaging CRAd and the trend for greater uptake by standardized uptake value analysis compared to control CRAd. In the aggregate, the plasticity of our dual imaging approach should provide the technical basis for monitoring CRAd biodistribution and persistence in preclinical studies while offering potential utility for a range of clinical applications

Derivation of a Triple Mosaic Adenovirus for Cancer Gene Therapy

A safe and efficacious cancer medicine is necessary due to the increasing population of cancer patients whose particular diseases cannot be cured by the currently available treatment. Adenoviral (Ad) vectors represent a promising therapeutic medicine for human cancer therapy. However, several improvements are needed in order for Ad vectors to be effective cancer therapeutics, which include, but are not limited to, improvement of cellular uptake, enhanced cancer cell killing activity, and the capability of vector visualization and tracking once injected into the patients. To this end, we attempted to develop an Ad as a multifunctional platform incorporating targeting, imaging, and therapeutic motifs. In this study, we explored the utility of this proposed platform by generating an Ad vector containing the poly-lysine (pK), the herpes simplex virus type 1 (HSV-1) thymidine kinase (TK), and the monomeric red fluorescent protein (mRFP1) as targeting, tumor cell killing, and imaging motifs, respectively. Our study herein demonstrates the generation of the triple mosaic Ad vector with pK, HSV-1 TK, and mRFP1 at the carboxyl termini of Ad minor capsid protein IX (pIX). In addition, the functionalities of pK, HSV-1 TK, and mRFP1 proteins on the Ad vector were retained as confirmed by corresponding functional assays, indicating the potential multifunctional application of this new Ad vector for cancer gene therapy. The validation of the triple mosaic Ad vectors also argues for the ability of pIX modification as a base for the development of multifunctional Ad vectors

HIV Antigen Incorporation within Adenovirus Hexon Hypervariable 2 for a Novel HIV Vaccine Approach

Adenoviral (Ad) vectors have been used for a variety of vaccine applications including cancer and infectious diseases. Traditionally, Ad-based vaccines are designed to express antigens through transgene expression of a given antigen. However, in some cases these conventional Ad-based vaccines have had sub-optimal clinical results. These sub-optimal results are attributed in part to pre-existing Ad serotype 5 (Ad5) immunity. In order to circumvent the need for antigen expression via transgene incorporation, the “antigen capsid-incorporation” strategy has been developed and used for Ad-based vaccine development in the context of a few diseases. This strategy embodies the incorporation of antigenic peptides within the capsid structure of viral vectors. The major capsid protein hexon has been utilized for these capsid incorporation strategies due to hexon's natural role in the generation of anti-Ad immune response and its numerical representation within the Ad virion. Using this strategy, we have developed the means to incorporate heterologous peptide epitopes specifically within the major surface-exposed domains of the Ad capsid protein hexon. Our study herein focuses on generation of multivalent vaccine vectors presenting HIV antigens within the Ad capsid protein hexon, as well as expressing an HIV antigen as a transgene. These novel vectors utilize HVR2 as an incorporation site for a twenty-four amino acid region of the HIV membrane proximal ectodomain region (MPER), derived from HIV glycoprotein gp41 (gp41). Our study herein illustrates that our multivalent anti-HIV vectors elicit a cellular anti-HIV response. Furthermore, vaccinations with these vectors, which present HIV antigens at HVR2, elicit a HIV epitope-specific humoral immune response

Study of e+e−→ppˉe^+e^- \rightarrow p\bar{p} in the vicinity of ψ(3770)\psi(3770)

Using 2917 $\rm{pb}^{-1}$ of data accumulated at 3.773~$\rm{GeV}$, 44.5~$\rm{pb}^{-1}$ of data accumulated at 3.65~$\rm{GeV}$ and data accumulated during a $\psi(3770)$ line-shape scan with the BESIII detector, the reaction $e^+e^-\rightarrow p\bar{p}$ is studied considering a possible interference between resonant and continuum amplitudes. The cross section of $e^+e^-\rightarrow\psi(3770)\rightarrow p\bar{p}$, $\sigma(e^+e^-\rightarrow\psi(3770)\rightarrow p\bar{p})$, is found to have two solutions, determined to be ($0.059\pm0.032\pm0.012$) pb with the phase angle $\phi = (255.8\pm37.9\pm4.8)^\circ$ ($<$0.11 pb at the 90% confidence level), or $\sigma(e^+e^-\rightarrow\psi(3770)\rightarrow p\bar{p}) = (2.57\pm0.12\pm0.12$) pb with $\phi = (266.9\pm6.1\pm0.9)^\circ$ both of which agree with a destructive interference. Using the obtained cross section of $\psi(3770)\rightarrow p\bar{p}$, the cross section of $p\bar{p}\rightarrow \psi(3770)$, which is useful information for the future PANDA experiment, is estimated to be either ($9.8\pm5.7$) nb ($<17.2$ nb at 90% C.L.) or $(425.6\pm42.9)$ nb

An epidemiological, developmental and clinical overview of cannabis use during pregnancy

The objective of the current narrative literature review is to provide an epidemiological, developmental and clinical overview on cannabis use during pregnancy. Cannabis use in pregnancy poses major health concerns for pregnant mothers and their developing children. Although studies on the short- and long-term consequences of prenatal cannabis exposure are increasing, findings have been inconsistent or difficult to interpret due to methodological issues. Thus, consolidating these findings into clinical recommendations based on the mixed studies in the literature remains a challenge. Synthesizing the available observational studies is also difficult, because some of the published studies have substantial methodological weaknesses. Improving observational studies will be an important step toward understanding the extent to which prenatal exposure to cannabis influences neurodevelopment in the offspring. Therefore, further research on prenatal cannabis exposure and the long-term consequences to offspring health in representative samples are needed to guide and improve clinical care for pregnant women and their children. Future research should also investigate the role of policies on prenatal cannabis use

Monitoring of Biodistribution and Persistence of Conditionally Replicative Adenovirus in a Murine Model of Ovarian Cancer Using Capsid-Incorporated mCherry and Expression of Human Somatostatin Receptor Subtype 2 Gene

A significant limiting factor to the human clinical application of conditionally replicative adenovirus (CRAd)-based virotherapy is the inability to noninvasively monitor these agents and their potential persistence. To address this issue, we proposed a novel imaging approach that combines transient expression of the human somatostatin receptor (SSTR) subtype 2 reporter gene with genetic labeling of the viral capsid with mCherry fluorescent protein. To test this dual modality system, we constructed the Ad5/3Δ24pIXcherry/SSTR CRAd and validated its capacity to generate fluorescent and nuclear signals in vitro and following intratumoral injection. Analysis of 64 Cu-CB-TE2A-Y3-TATE biodistribution in mice revealed reduced uptake in tumors injected with the imaging CRAd relative to the replication-incompetent, Ad-expressing SSTR2 but significantly greater uptake compared to the negative CRAd control. Optical imaging demonstrated relative correlation of fluorescent signal with virus replication as determined by viral genome quantification in tumors. Positron emission tomography/computed tomography studies demonstrated that we can visualize radioactive uptake in tumors injected with imaging CRAd and the trend for greater uptake by standardized uptake value analysis compared to control CRAd. In the aggregate, the plasticity of our dual imaging approach should provide the technical basis for monitoring CRAd biodistribution and persistence in preclinical studies while offering potential utility for a range of clinical applications